Novel compounds as modulators of protein kinases

ABSTRACT

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

This application is a continuation of U.S. patent application Ser. No.16/359,419, filed Mar. 20, 2019 which is a divisional of U.S. patentapplication Ser. No. 15/677,614, filed Aug. 15, 2017, which is acontinuation of U.S. patent application Ser. No. 13/464,587, filed May4, 2012, now U.S. Pat. No. 9,775,841, which claims the benefit of IndianProvisional Patent Application Nos. 1542/CHE/2011 dated 4 May 2011 and81/CHE/2012 dated 9 Jan. 2012, each of which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention provides PI3K protein kinase modulators, methodsof preparing them, pharmaceutical compositions containing them andmethods of treatment, prevention and/or amelioration of kinase mediateddiseases or disorders with them.

BACKGROUND OF THE INVENTION

In the recent past immense research has been dedicated to the discoveryand understanding of the structure and functions of enzymes andbio-molecules associated with various diseases. One such important classof enzymes that has been the subject of extensive research is ProteinKinase.

In general, protein kinases represent a set of structurally relatedphosphoryl transferases having conserved structures and catalyticfunctions. These enzymes modify proteins by chemically adding phosphategroups (phosphorylation). Phosphorylation involves the removal of aphosphate group from ATP and covalently attaching it to amino acids thathave a free hydroxyl group such as serine, threonine or tyrosine.Phosphorylation usually results in a functional change of the targetprotein (substrate) by altering enzyme activity, cellular localizationor association with other proteins. Up to 30% of all proteins may bemodified by kinase activity.

This class of proteins are classified into subsets depending upon thesubstrate they act upon such as tyrosine kinase, serine/theroninekinase, histidine kinase and the like. These proteins can also beclassified based on their localization into receptor tyrosine kinases(RTKs) or non-receptor tyrosine kinases.

Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. Receptor tyrosine kinasemediated signal transduction is typically initiated by an extracellularinteraction with a specific growth factor (ligand), followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and phosphorylation of amino acid residues. The ensuingconformational change leads to the formation of complexes with aspectrum of cytoplasmic signalling molecules and facilitates a myriad ofresponses such as cell division, differentiation, metabolic effects, andchanges in the extracellular microenvironment.

Protein kinases are known to control a wide variety of biologicalprocesses such as cell growth, survival and differentiation, organformation and morphogenesis, neovascularisation, tissue repair andregeneration. In addition to their functions in normal tissues/organs,many protein kinases also play specialized roles in a host of humandiseases including cancer. A subset of protein kinases (also referred toas oncogenic protein kinases), when dysregulated, can cause tumorformation and growth and contribute to tumor maintenance and progression(Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,oncogenic protein kinases represent one of the largest and mostattractive groups of protein targets for therapeutic intervention anddrug development.

Both receptor and non-receptor protein kinases have been found to beattractive targets for small molecule drug discovery due to their impacton cell physiology and signalling. Dysregulation of protein kinaseactivity thus leads to altered cellular responses including uncontrolledcell growth associated with cancer. In addition to oncologicalindications, altered kinase signalling is implicated in numerous otherpathological diseases. These include, but are not limited toimmunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, the two key cellular processes needed for tumor growth andsurvival is an attractive goal for development of small-molecule drugs(Matter A. Drug Disc Technol 2001, 6, 1005-1024). Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularisation including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. Similarly, cellantiproliferative agents are desirable to slow or inhibit the growth oftumors.

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. Cell signaling via 3-phosphorylated phosphoinositides hasbeen implicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsiblefor generating these phosphorylated signaling products,phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K),was originally identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylate phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3-hydroxyl of the inositol ring (Panayotou et al(1992) Trends Cell Biol 2:358-60).

The phosphoinositide 3-kinases (PI3Ks) are a family of enzymes thatregulate diverse biological functions in every cell type by generatingphosphoinositide second-messenger molecules. As the activity of thesephosphoinositide second messengers is determined by theirphosphorylation state, the kinases and phosphatises that act to modifythese lipids are central to the correct execution of intracellularsignaling events. Phosphoinositide 3-kinases (PI3K) phosphorylate lipidsat the 3-hydroxyl residue of an inositol ring (Whitman et al (1988)Nature, 332:664) to generate phosphorylated phospholipids (PIP3s) whichact as second messengers recruiting kinases with lipid binding domains(including plekstrin homology (PH) regions), such as Akt andphosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membranePIP3s causes the translocation of Akt to the plasma membrane, bringingAkt into contact with PDK1, which is responsible for activating Akt. Thetumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and thereforeacts as a negative regulator of Akt activation. The PI3-kinases Akt andPDK1 are important in the regulation of many cellular processesincluding cell cycle regulation, proliferation, survival, apoptosis andmotility and are significant components of the molecular mechanisms ofdiseases such as cancer, diabetes and immune inflammation (Vivanco et al(2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).

The PI3K family is constituted by four different classes: classes I, IIand III are lipid kinases while members of class IV are Ser/Thr proteinkinases.

The members of the class I family of PI3Ks are dimers of a regulatoryand a catalytic subunit. The class I family consists of four isoforms,determined by the catalytic subunits α, β, γ and δ (see Engelman J A,Nat Rev Genet 2006; 7:606-19; Carnero A, Curr Cancer Drug Targets 2008;8:187-98; Vanhaesebroeck B, Trends Biochem Sci 2005; 30:194-204). ClassI can be subdivided into two subclasses: Ia, formed by the combinationof p110 α β and δ and a regulatory subunit (p85, p55 or p50) and Ib,formed by p110 γ and p101 regulatory subunits. The regulatory subunitp85 contains Src homology 2 domains, which bind to phosphotyrosines andbring the attached catalytic subunit p110 into the complexes located inthe membrane around the receptor. The activation of PI3K is induced bygrowth factors and insulin targeting the catalytic subunit to themembrane where it is in close proximity with its substrates, mainlyPIP2. Alternatively, GTP-bound Ras can bind and activate p110 subunitsin a p85-independent manner. Class I phosphoinositide 3-kinases (PI3Ks)are lipid kinases that phosphorylate phosphatidyl-inositide lipids (PI)at the D3 position of the inositol ring producing lipid secondmessengers (PIPs). The products of PI3K activity, mainly PI(3,4,5)-P3(PIP3), are present in very low level in quiescent cells but are rapidlyproduced during cell stimulation and are involved in the regulation ofseveral biological responses including mitogenesis, apoptosis, vesiculartrafficking and cytoskeleton rearrangement. The result of rising PIP3levels is the activation of 3-phosphoinositide-dependent proteinkinase-1 and its substrate AKT, which triggers most of the biologicalactivities of the pathway. Phosphatase and tensin homolog in chromosome10 (PTEN) is a lipidic phosphatase which constitutes the main negativeregulator of the route by dephosphorylating PIP3 to PI(4,5)-P2 (PIP2).Class II displays the ability to phosphorylate PI and PI-4 phosphate invitro. Class III, composed by Vps34 only member, phosphorylates PI atposition 3 generating PI 3-phosphate. Vps34 has been implicated in Golgitrafficking of proteins, autophagy and activation of mammalian target ofrapamycin (mTOR) by amino acids (see Backer J M. Biochem J 2008;410:1-17). These classes are generally resistant to class I PI3Kinhibitors. Class IV, however, is important because it constitutes themajor cross-activity proteins for class I inhibitors. This classincludes enzymes involved in signal transduction and DNA damage responsesuch as mTOR, DNA-dependent protein kinase (DNA-PK) or ATM. This fourthclass of PI3K-related enzymes contains a catalytic core similar to thePI3K, which can account for the cross-inhibition by class I ‘selective’compounds. However, small differences, especially in the hinge region,and the solving of the PI3K-related structures might lead to the finetuning of different paralog selective PI3K-members. (see Expert Opin.Investig. Drugs (2009) 18(9): 1265-1277)

There is now considerable evidence indicating that Class Ia PI3K enzymescontribute to tumourigenesis in a wide variety of human cancers, eitherdirectly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer,2002, 2, 489-501). For example, the pi 10a subunit is amplified in sometumours such as those of the ovary (Shayesteh et al, Nature Genetics.1999, 21: 99-102) and cervix (Ma et al, Oncogene, 2000, 19: 2739-2744).More recently, activating mutations within the catalytic site of pi 10ahave been associated with various other tumours such as those of thecolorectal region and of the breast and lung (Samuels et al, Science,2004, 304, 554). Tumour-related mutations in p85α have also beenidentified in cancers such as those of the ovary and colon (Philp etal., Cancer Research, 2001, 61, 7426-7429). In addition to directeffects, it is believed that activation of Class Ia PI3K contributes totumourigenic events that occur upstream in signalling pathways, forexample by way of ligand-dependent or ligand-independent activation ofreceptor tyrosine kinases, GPCR systems or integrins (Vara et al, CancerTreatment Reviews, 2004, 30, 193-204). Examples of such upstreamsignalling pathways include over-expression of the receptor tyrosinekinase Erb2 in a variety of tumours leading to activation ofPI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114)and over-expression of the oncogene Ras (Kauffmann-Zeh et al., Nature,1997, 385, 544-548). In addition, Class Ia PBKs may contributeindirectly to tumourigenesis caused by various downstream signallingevents. For example, loss of the effect of the PTEN tumour-suppressorphosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2is associated with a very broad range of tumours via deregulation ofPI3K-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. CellRes. 2001, 264, 29-41). Furthermore, augmentation of the effects ofother PI3K-mediated signalling events is believed to contribute to avariety of cancers, for example by activation of Akt (Nicholson andAnderson, Cellular Signalling, 2002, H, 381-395).

In addition to a role in mediating proliferative and survival signallingin tumour cells, there is also good evidence that Class Ia PI3K enzymeswill also contribute to tumourigenesis via its function intumour-associated stromal cells. For example, PI3K signalling is knownto play an important role in mediating angiogenic events in endothelialcells in response to pro-angiogenic factors such as VEGF (Abid et al.,Arterioscler. Thromb. Vase. Biol., 2004, 24, 294-300). As Class I PI3Kenzymes are also involved in motility and migration (Sawyer, ExpertOpinion Investig. Drugs, 2004, JJ., 1-19), PI3K inhibitors shouldprovide therapeutic benefit via inhibition of tumour cell invasion andmetastasis.

In addition, Class I PI3K enzymes play an important role in theregulation of immune cells with PI3K activity contributing topro-tumourigenic effects of inflammatory cells (Coussens and Werb,Nature, 2002, 420, 860-867). These findings suggest that pharmacologicalinhibitors of Class I PI3K enzymes should be of therapeutic value fortreatment of the various forms of the disease of cancer comprising solidtumours such as carcinomas and sarcomas and the leukaemias and lymphoidmalignancies. In particular, inhibitors of Class I PI3K enzymes shouldbe of therapeutic value for treatment of, for example, cancer of thebreast, colorectum, lung (including small cell lung cancer, non-smallcell lung cancer and bronchioalveolar cancer) and prostate, and ofcancer of the bile duct, bone, bladder, head and neck, kidney, liver,gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes,thyroid, uterus, cervix and vulva, and of leukaemias (including ALL andCML), multiple myeloma and lymphomas.

A recent review by Romina Marone et. al., Biochimica et Biophysica Acta1784 (2008) 159-185, describes the activation of the PI3K signallingcascade having a positive effect on cell growth, survival andproliferation. Constitutive up-regulation of PI3K signaling can have adeleterious effect on cells leading to uncontrolled proliferation,enhanced migration and adhesion-independent growth. These events favornot only the formation of malignant tumors, but also the development ofinflammatory and autoimmune disease indicating the role of PI3K invarious diseases including chronic inflammation & allergy,Cardiovascular diseases, cancer and metabolic disorders.

Several components of the PI3-kinase/Akt/PTEN pathway are implicated inoncogenesis. In addition to growth factor receptor tyrosine kinases,integrin-dependent cell adhesion and G-protein coupled receptorsactivate PI3-kinase both directly and indirectly through adaptormolecules. Functional loss of PTEN (the most commonly mutatedtumor-suppressor gene in cancer after p53), oncogene mutations in PI3kinase (Samuels et al (2004) Science 304:554), amplification ofPI3-kinase and overexpression of Akt have been established in manymalignancies. In addition, persistent signaling through thePI3-kinase/Akt pathway by stimulation of the insulin-like growth factorreceptor is a mechanism of resistance to epidermal growth factorreceptor inhibitors such as AG1478 and trastuzumab. Oncogenic mutationsof p110alpha have been found at a significant frequency in colon,breast, brain, liver, ovarian, gastric, lung, and head and neck solidtumors. PTEN abnormalities are found in glioblastoma, melanoma,prostate, endometrial, ovarian, breast, lung, head and neck,hepatocellular, and thyroid cancers.

The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), theprimary product of PI3-kinase activation, increase upon treatment ofcells with a variety of agonists. PI3-kinase activation, therefore, isbelieved to be involved in a range of cellular responses including cellgrowth, differentiation, and apoptosis (Parker et al (1995) CurrentBiology, 5:577-99; Yao et al (1995) Science, 267:2003-05). Though thedownstream targets of phosphorylated lipids generated following PI3kinase activation have not been well characterized, emerging evidencesuggests that pleckstrin-homology domain- and FYVE-fingerdomain-containing proteins are activated when binding to variousphosphatidylinositol lipids (Sternmark et al (1999) J Cell Sci,112:4175-83; Lemmon et al (1997) Trends Cell Biol, 7:237-42). In vitro,some isoforms of protein kinase C (PKC) are directly activated by PIP3,and the PKC-related protein kinase, PKB, has been shown to be activatedby PI3 kinase (Burgering et al (1995) Nature, 376:599-602).

PI3 kinase also appears involved in leukocyte activation. Ap85-associated PI3 kinase activity has been shown to physicallyassociate with the cytoplasmic domain of CD28, which is an importantcostimulatory molecule for the activation of T-cells in response toantigen (Pages et al (1994) Nature, 369:327-29; Rudd, (1996) Immunity4:527-34). Activation of T cells through CD28 lowers the threshold foractivation by antigen and increases the magnitude and duration of theproliferative response. These effects are linked to increases in thetranscription of a number of genes including interleukin-2 (IL2), animportant T cell growth factor (Fraser et al (1991) Science,251:313-16). Mutation of CD28 such that it can no longer interact withPI3 kinase leads to a failure to initiate IL2 production, suggesting acritical role for PI3 kinase in T cell activation.

Inhibition of class I PI3 kinase induces apoptosis, blocks tumor inducedangiogenesis in vivo, and increases the radiosensitivity of certaintumors. At least two compounds, LY294002 and wortmannin, have beenwidely used as PI3 kinase inhibitors. These compounds, however, arenonspecific PI3K inhibitors, as they do not distinguish among the fourmembers of Class I PI3 kinases. For example, the IC50 values ofwortmannin (U.S. Pat. No. 6,703,414) against each of the various Class IPI3 kinases are in the range of 1-10 nanomolar (nM). LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is a well knownspecific inhibitor of class I PI3 kinases and has anti-cancer properties(Chiosis et al (2001) Bioorganic & Med. Chem. Lett. 11:909-913; Vlahoset al (1994) J. Biol. Chem. 269(7):5241-5248; Walker et al (2000) Mol.Cell 6:909-919; Fruman et al (1998) Ann Rev Biochem, 67:481-507).

Patent literature belonging to various research groups around the worldincludes several such patents and/or patent applications viz., U.S. Pat.Nos. 6,608,056; 6,608,053; 6,838,457; 6,770,641; 6,653,320; 6,403,588;WO 2004017950; US 2004092561; WO 2004007491; WO 2004006916; WO2003037886; US 2003149074; WO 2003035618; WO 2003034997; US 2003158212;EP 1417976; US 2004053946; JP 2001247477; JP 08175990; JP 08176070). WO97/15658, U.S. Pat. Nos. 7,173,029; 7,037,915; 6,703,414; WO2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491;WO2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO2003/034997; including p110 alpha binding activity US 2008/0207611; US2008/0039459; US 2008/0076768; WO 2008/073785; WO 2008/070740;US20090270430A1; US2006270673 A1; WO2009129211A1; US2009 0263398A1;US20090263397A1; WO2009129259A2; U.S. Pat. Nos. 7,605,160; 7,605,155;7,608,622; US20090270621; US20090270445; US20090247567A1; U.S. Pat. No.7,592,342; US2009 0239847A1; U.S. Pat. No. 7,595,320; US20090247538A1;US20090239936A1; U.S. Pat. No. 7,595,330; US20090239859A1;WO2009117482A1; WO2009117097A1; US20090247565A1; WO2009 120094A2;US20090258852A1; U.S. Pat. No. 7,601,724; WO2009126635A1; U.S. Pat. Nos.7,601,718; 7,598,245; US20090239859A1; US20090247554; US20090238828;WO2009114874A2; WO2009114870A2; US20090234132A1; WO2009112565A1;US20090233950A1; US20090233926A1; U.S. Pat. No. 7,589,101;WO2009111547A1; WO2009111531A1; WO2009109867A2 and WO2009105712A1.

Reviews and studies regarding PI3K and related protein kinase pathwayshave been given by Pixu Liu et. al. (Nature Reviews Drug Discovery,2009, 8, 627-644); Nathan T. et. al. (Mol Cancer Ther., 2009; 8 (1)January, 2009); Romina Marone et, al. (Biochimica et Biophysica Acta1784 (2008) 159-185) and B. Markman et. al. (Annals of oncology Advanceaccess published August 2009). All of these patents and/or patentapplications and literature disclosures are incorporated herein asreference in their entirety for all purposes.

There still remains an unmet and dire need for small molecule kinasemodulators in order to regulate and/or modulate transduction of kinases,particularly PI3K and related protein kinase for the treatment ofdiseases and disorders associated with kinases-mediated events.

Further a reference is made herein to International patent ApplicationNo. PCT/IB2010/002804, filed Nov. 3, 2010, and U.S. patent applicationSer. No. 12/938,609 filed Nov. 3, 2010 which generally disclose 2,3disubstituted-4H-chromen-4-one and are incorporated herein by referencein their entirety for all purposes.

SUMMARY OF INVENTION

The present invention is directed to compounds, which are useful as PI3Kprotein kinase modulators and in particular as PI3K inhibitors. In oneembodiment, the compound of the present invention has the formula:

wherein

each occurrence of R is independently selected from hydroxy, halogen,carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, —COOR^(x), —C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y),—C(O)ONR^(x)R^(y), —NR^(x)R^(y), —NR^(x)CONR^(x)R^(y), —N(R^(x))SOR^(x),—N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y),—NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y),—SONR^(x)R^(y)—, —SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(x)R^(y),—OR^(x)C(O)OR^(x)—, —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),—R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), —ONO₂, wherein R^(x), R^(y) and R^(z) in each ofthe above groups can be hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted heterocyclylalkyl ring, or substituted or unsubstitutedamino, or (i) any two of R^(x) and R^(y) may be joined to form asubstituted or unsubstituted, saturated or unsaturated 3-14 memberedring, which may optionally include heteroatoms which may be the same ordifferent and are selected from O, NR^(z) or S, or (ii) any two of R^(x)and R^(y) join to form a oxo (═O), thio (═S) or imino (═NR^(f)) (whereinR^(f) is hydrogen or substituted or unsubstituted alkyl).

R¹ and R² may be the same or different and are independently selectedfrom hydrogen, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyland substituted or unsubstituted heterocyclyl or both R¹ and R² directlybound to a common atom, may be joined to form an oxo group (═O) or asubstituted or unsubstituted, saturated or unsaturated 3-10 member ring(including the carbon atom to which R¹ and R² are bound), which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR^(a) and S;

Cy¹ is selected from substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl;

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl;

L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—,—NR^(a)— or —C(═Y)—.

each occurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR′(wherein R^(c) is substituted or unsubstituted (C₁₋₆)alkyl) or whenR^(a) and R^(b) are directly bound to a common atom, they may be joinedto form an oxo group (═O) or form a substituted or unsubstituted,saturated or unsaturated 3-10 member ring (including the common atom towhich R^(a) and R^(b) are directly bound), which may optionally includeone or more heteroatoms which may be the same or different and areselected from O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S;

Y is selected from O, S, and NR^(a); and

q is 0, 1 or 2

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof.

Yet another embodiment is a compound having the formula (I-A)

wherein

each occurrence of R is independently selected from halogen, CN,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈cycloalkyl, and substituted or unsubstituted heterocyclic group;

R¹ and R² may be the same or different and are independently selectedfrom hydrogen, halogen, and substituted or unsubstituted C₁₋₆ alkyl, orboth R¹ and R² directly bound to a common atom, may be joined to form anoxo group (═O) or a substituted or unsubstituted, saturated orunsaturated 3-10 member ring (including the carbon atom to which R¹ andR² are bound), which may optionally include one or more heteroatomswhich may be the same or different and are selected from O, NR^(a) andS;

Cy¹ is a monocyclic group selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl;

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl;

L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—,—NR^(a)— or —C(═Y)—.

each occurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl or (C₁₋₆)alkoxy) and —OR′(wherein R^(c) is substituted or unsubstituted (C₁₋₆)alkyl) or whenR^(a) and R^(b) are directly bound to a common atom, they may be joinedto form an oxo group (═O) or form a substituted or unsubstituted,saturated or unsaturated 3-10 member ring (including the common atom towhich R^(a) and R^(b) are directly bound), which may optionally includeone or more heteroatoms which may be the same or different and areselected from O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S;

Y is selected from O, S, and NR^(a); and

q is 0, 1 or 2

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof.

Yet another embodiment is a compound having the formula (I) or (IA)wherein R is selected from halogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₈ cycloalkyl, and substituted orunsubstituted heterocyclic group or OR^(a).

Yet another embodiment is a compound having the formula (I) or (IA)wherein R is selected from fluoro, methyl, morpholine or —OCH₃.

Further preferred is a compound having the formula (I) or (IA) whereinCy¹ is selected from substituted or unsubstituted aryl and substitutedor unsubstituted heteroaryl.

Illustrative examples of optionally substituted Cy¹ groups include thoseshown below:

Further preferred is a compound having the formula (I) or (IA), whereinCy¹ is selected from

Further preferred is a compound having the formula (I) or (IA), whereinCy¹ is substituted or unsubstituted phenyl or pyrazole.

Further preferred is a compound having the formula (I) or (IA) whereinCy¹ is substituted phenyl.

Further preferred is a compound having the formula (I) or (IA), whereinCy¹ is 2-methyl phenyl, 2-fluoro phenyl, 3-fluoro phenyl, 4-fluorophenyl or pyrazol-4-yl.

Yet another embodiment is a compound having the formula (I) or (IA),wherein R¹ and R² independently represent hydrogen or substituted orunsubstituted C₁₋₆ alkyl (for example, methyl).

Yet another embodiment is a compound having the formula (I) or (IA),wherein L₁ is selected from —S(═O)_(q)— or —NR^(a).

Yet another embodiment is a compound having the formula (I) or (IA),wherein q is 0.

Yet another embodiment is a compound having the formula (I) or (IA),wherein R^(a) hydrogen.

Yet another embodiment is a compound having the formula (I) or (IA),wherein L₁ is absent.

Yet another embodiment is a compound having the formula (I) or (IA),wherein L₁-Cy² is selected from

wherein

X is CR³; and

each occurrence of R³ is independently selected from hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocyclic ring, or unsubstituted heterocyclyalkyl ring, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted guanidine, —COOR^(x),—C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(y)R^(z), —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),-(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y) —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), or —ONO₂, wherein R^(x),R^(y) and R^(z) in each of the above groups can be hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclicring, substituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or any two of R^(x), R^(y) and R^(z) may be joinedto form a substituted or unsubstituted, saturated or unsaturated 3-10membered ring, which may optionally include heteroatoms which may be thesame or different and are selected from O, NR^(f) or S (wherein R^(f) ishydrogen or substituted or unsubstituted alkyl).

Yet another embodiment is a compound having the formula (I) and (IA),wherein L₁-Cy² is selected from

wherein

X and R³ are the same as defined above; and

each occurrence of R′ and R″ is independently selected from hydrogen,hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocyclylalkyl ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—, —SO₂NR^(x)R^(y)—, —OR^(x),—OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—, —OC(O)R^(x),—OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, or both theR′ and R″ together with the nitrogen atom may be joined to form asubstituted or unsubstituted, saturated or unsaturated 3-10 memberedring, which may optionally include heteroatoms which may be the same ordifferent and are selected from O, NR^(f) (wherein R^(f) is hydrogen orsubstituted or unsubstituted alkyl) or S;

R^(x), R^(y) and R^(z) in each of the above groups can be hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclicring, substituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or any two of R^(x), R^(y) and R^(z) may be joinedto form a substituted or unsubstituted, saturated or unsaturated 3-10membered ring, which may optionally include heteroatoms which may be thesame or different and are selected from O, NR^(f) or S (wherein R^(f) ishydrogen or substituted or unsubstituted alkyl); and

q is 0, 1 or 2.

Yet another embodiment is a compound having the formula (I) and (IA),wherein L₁-Cy² is selected from

wherein

X and R³ are the same as defined above.

For example, L₁-Cy² is represented as formula a, b c, d e, or f abovecan be

Yet another embodiment is a compound having the formula (I) and (IA)wherein L₁-Cy² is selected from

Yet another embodiment is a compound having the formula (I) or (IA)wherein L₁-Cy² is selected from

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV) or (IA-V).

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof,wherein:

R is selected from hydrogen, halogen, —OR^(a), CN, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, and substituted or unsubstituted heterocyclic group;

R¹ and R² may be the same or different and are independently selectedfrom hydrogen, halogen, and substituted or unsubstituted C₁₋₆ alkyl orboth R¹ and R² directly bound to a common atom, may be joined to form anoxo group (═O) or may be joined to form a substituted or unsubstitutedsaturated or unsaturated 3-10 member ring (including the common atom towhich R¹ and R² are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(a) and S;

Cy¹ is a monocyclic group selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl;

each occurrence of X is independently selected from CR³ or N;

each occurrence of R³ is independently selected from hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocyclic ring, or unsubstituted heterocyclyalkyl ring, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted guanidine, —COOR^(x),—C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(y)R^(z), —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R′)SO₂R^(y),-(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y) —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), or —ONO₂, wherein R^(x),R^(y) and R^(z) in each of the above groups can be hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclicring, substituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or any two of R^(x), R^(y) and R^(z) may be joinedto form a substituted or unsubstituted, saturated or unsaturated 3-10membered ring, which may optionally include heteroatoms which may be thesame or different and are selected from O, NR^(f) (wherein R^(f) ishydrogen or substituted or unsubstituted alkyl) or S; and

q is 0, 1 or 2.

Yet another embodiment is a compound having the formula (IA-Ia),(IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb).

wherein X, R³, R′ and R″ are the same as defined above.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb) wherein R is selected from hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl, OR^(a) or morpholine.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb) wherein R is selected from hydrogen, halogen, OR^(a) ormorpholine.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb) wherein Cy¹ is selected from

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb) wherein R¹ and R² independently represent hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl

Yet another embodiment is a compound having the formula (IA-II),(IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) wherein R³ is selected fromiodo, cyano, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

Yet another embodiment is a compound having the formula (IA-II),(IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) wherein R³ is selected fromsubstituted or unsubstituted alkynyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl

Yet another embodiment is a compound having the formula (IA-II),(IA-III), (IA-IIa), (IA-IIIa) or (IA-IIb) wherein R³ is selected from

wherein

each occurrence of X is independently CR⁴ or N;

X¹ is O, S, or NR⁴; and

each occurrence of R⁴ is independently selected from hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocyclic ring, or unsubstituted heterocyclyalkyl ring, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted guanidine, —COOR^(x),—C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(y)R^(z), —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),-(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y) —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), or —ONO₂, wherein R^(x),R^(y) and R^(z) in each of the above groups can be hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclicring, substituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or any two of R^(x), R^(F) and R^(z) may be joinedto form a substituted or unsubstituted, saturated or unsaturated 3-10membered ring, which may optionally include heteroatoms which may be thesame or different and are selected from O, NR^(f) (wherein R^(f) ishydrogen or substituted or unsubstituted alkyl) or S;

For example, R³ can be any one of the following:

Yet another embodiment is a compound having the formula (IA-III) or(IA-IIIa) wherein R³ is selected from iodo, cyano and substituted orunsubstituted alkynyl.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III), (IA-IV), (IA-V), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb) wherein X is CR³ and each occurrence of R³ is independentlyhydrogen, halogen, hydroxyl or NH₂.

Yet another embodiment is a compound of formula (IA-VI)

or a pharmaceutically acceptable salt thereof, wherein

R, R¹, R², R³, R′, R″ and X are as defined above with respect to any offormulas (I), (IA) or (IA-II);

each occurrence of R⁵ is hydrogen, C₁₋₆ alkyl or halogen; and

p is 0, 1, 2, 3, 4 or 5.

Yet another embodiment is a compound having the formula (IA-II) or(IA-VI) wherein R³ is selected from

Yet another embodiment is a compound of formula (IA-VII)

or a pharmaceutically acceptable salt thereof, wherein

R, R¹, R², R³ and X are as defined above with respect to any of formulas(I), (IA) or (IA-III);

each occurrence of R⁵ is hydrogen, C₁₋₆ alkyl or halogen; and

p is 0, 1, 2, 3, 4 or 5.

Yet another embodiment is a compound having the formula (IA-VII) whereinR³ is halogen or cyano.

Yet another embodiment is a compound of formula (IA-VIII)

or a pharmaceutically acceptable salt thereof, wherein

R, R¹, R² and X are as defined above with respect to any of formulas areas defined above with respect to any of formulas (I), (IA) or (IA-IV);

each occurrence of R⁵ is hydrogen, C₁₋₆ alkyl or halogen; and

p is 0, 1, 2, 3, 4 or 5.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein R is halogen (such as fluoro) or C₁₋₆alkyl (such as methyl).

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein p is 0.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein p is 1 and R⁵ is 3-fluoro, 2-fluoro,4-fluoro or 2-methyl.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein R¹ is methyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein R¹ is ethyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein R¹ and R² are hydrogen.

Yet another embodiment is a compound having the formula (IA-VI),(IA-VII) or (IA-VIII) wherein X is C—H, C—F, C—Cl, C—NH₂ or C—OH.

Further preferred is a compound having the formula (IA-VI), (IA-VII) or(IA-VIII) wherein X is C—H.

Yet another embodiment is a compound having the formula (IA-VI) whereineach of R′ and R″ is selected from is hydrogen or C₁₋₆ alkyl (such asmethyl).

Yet another embodiment is a compound having the formula (IA-VI) wherein—NR′R″ together represents

Representative compounds of the present invention include thosespecified below and pharmaceutically acceptable salts thereof. Thepresent invention should not be construed to be limited to them.

-   1. 2-(6-Amino-9H-purin-9-yl)    methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one-   2.    2-((4-Amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one-   3.    2-((4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   4.    2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   5.    2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   6.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   7.    (+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   8.    (−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   9.    2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   9a.    (+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   9b.    (−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   10.    2-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   11.    2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   12.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   13.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   14.    2-(1-(4-amino-3-(benzofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   15.    2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   16.    2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   16a.    (+)-2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   16b.    (−)-2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   17.    2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   18.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one-   19.    2-(1-(4-amino-3-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   20.    2-(1-(4-amino-3-(3-isopropyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   21.    2-(1-(4-amino-3-(3-fluoro-4-(piperidin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   22.    2-(1-(4-amino-3-(3-fluoro-4-(2-hydroxyethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   23.    2-(1-(4-amino-3-(3-fluoro-4-(isopropylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   24.    2-(1-(4-amino-3-(4-(dimethylamino)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   25.    2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   26.    2-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   27.    2-(1-(4-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   28.    2-(1-(4-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   29.    2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   30.    2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   31.    2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   32.    2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   33.    2-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   34.    2-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   35.    2-(1-(4-amino-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   36.    2-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   37.    2-(1-(4-amino-3-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   38.    2-(1-(4-amino-3-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   39.    2-(1-(4-amino-3-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   40.    2-(1-(4-amino-3-(6-isopropoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   41.    2-(1-(4-amino-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   42.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    4-methylbenzenesulfonate-   43.    2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    4-methylbenzenesulfonate-   44.    2-(1-(4-amino-3-(4-(1-benzhydrylazetidin-3-yloxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   45.    2-(1-(4-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   46.    2-(1-(4-amino-3-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   47.    2-(1-(4-amino-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   48.    N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide-   49.    2-(1-(4-amino-3-(4-isobutylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   50.    2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   51.    2-(1-(4-amino-3-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   52.    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzenesulfonamide-   53.    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-N-isopropylbenzamide-   54.    2-(1-(4-amino-3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   55.    N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methanesulfonamide-   56.    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzenesulfonamide-   57.    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzenesulfonamide-   58.    2-(1-(4-amino-3-(2-isopropoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   59.    (R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   60.    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzenesulfonamide-   61. methyl    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carboxylate-   62.    2-(1-(4-amino-3-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   63.    2-(1-(4-amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   64. methyl    4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorobenzoate-   65.    2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   66.    2-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   67.    (S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    4-methylbenzenesulfonate-   68.    (+)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   69.    2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   70.    (R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   71.    2-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   72.    2-(1-(4-amino-3-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    or-   73.    2-(1-(4-amino-3-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   74. tert-butyl    (5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamate-   75.    2-(1-(4-amino-3-(2,4-dimethylthiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   76.    2-(1-(4-amino-3-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   77.    2-(1-(4-amino-3-(4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   78.    (−)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   79.    2-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   80.    2-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   81.    N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)isobutyramide-   82.    N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamide-   83.    2-(1-(4-(dimethylamino)-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   84.    5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one-   85.    5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one-   86.    N-(2-fluoro-4-(1-(1-(5-fluoro-3-(4-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide-   87.    N-(2-fluoro-4-(1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide-   88.    (S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    sulphate 89.    (S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   90.    (S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    camphorsulphonate-   91.    2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one-   92.    2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   93.    2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   94. and 95.    (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one    and    (R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one.-   96. and 97.    (S)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one    and    (R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   98.    2-(1-(4-(dimethylamino)-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   99.    5-fluoro-2-(1-(3-(3-fluoro-4-morpholinophenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one-   100. and 101.    (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one    and    (R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one.-   102. and 103.    (S)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one    and    (R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one-   104.    (+)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one    and-   105.    (−)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one.-   106.    2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   107.    2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one-   108.    5-fluoro-3-(4-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one-   109.    5-fluoro-3-(4-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one-   110.    2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   111.    2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   112.    5-fluoro-3-(3-fluorophenyl)-2-(1-(3-(3-methyl-1H-indazol-6-yl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one-   113.    2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   114.    (+)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   115.    (−)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   116.    (S)/(R)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one-   117.    2-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   118.    2-(1-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   119.    5-fluoro-3-(3-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one-   120.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-5-morpholino-4H-chromen-4-one-   121.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-morpholino-3-phenyl-4H-chromen-4-one-   122.    6-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one-   123.    5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one-   124.    2-(1-(3-(4-acetyl-3-fluorophenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   125.    5-fluoro-3-(3-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one-   126. and 127.    (S)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    and    (R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   128.    N-(3-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide-   129. and 130.    (S)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one    and    (R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   131.    2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one-   132.    2-(1-(4-amino-3-(4-ethoxy-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   133.    2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one-   134. and 135.    (S)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one    and    (R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one.-   136.    (S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluoro    phenyl)-4H-chromen-4-one-   137.    (S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one-   138.    2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-o-tolyl-4H-chromen-4-one    and pharmaceutically acceptable salts thereof

TABLE 1 Ex. Structure  1.

 2.

 3.

 4.

 5.

 6.

  6a.

  6b.

 7.

 8.

 9.

  9a.

  9b.

 10.

 11.

 12.

 13.

 14.

 15.

 16.

 16a.

 16b.

 17.

 18.

 19.

 20.

 21.

 22.

 23.

 24.

 25.

 26.

 27.

 28.

 29.

 30.

 31.

 32.

 33.

 34.

 35.

 36.

 37.

 38.

 39.

 40.

 41.

 42.

 43.

 44.

 45.

 46.

 47.

 48.

 49.

 50.

 51.

 52.

 53.

 54.

 55.

 56.

 57.

 58.

 59.

 60.

 61.

 62.

 63.

 64.

 65.

 66.

 67.

 68.

 69.

 70.

 71.

 72.

 73.

 74.

 75.

 76.

 77.

 78.

 79.

 80.

 81.

 82.

 83.

 84.

 85.

 86.

 87.

 88.

 89.

 90.

 91.

 92.

 93.

 94.

 95.

 96.

 97.

 98.

 99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

Yet another embodiment of the present invention is a compound of formula

wherein the variables are the same as defined above.

Yet another embodiment of the present invention is a process forpreparing the compound of formula

comprising the steps as depicted in scheme 1 below.

Yet another embodiment of the present invention is a compound of formula

wherein the variables are the same as defined above.

Yet another embodiment of the present invention is a process forpreparing the compound of formula

comprising the steps as depicted and described in scheme 1A below.

Yet another embodiment of the present invention is a process forpreparing the compound of formula (I) comprising the steps of convertinga compound of formula (10) as depicted and described in Scheme 2, 3 or 4below.

Yet another embodiment of the present invention is a process forpreparing the compound of formula (I) comprising the steps of convertingcompound of formula (12) as depicted and described in Scheme 2, 3 or 4below.

Yet another embodiment of the present invention is a process forpreparing the compound of formula (10), (14) or (15) comprising thesteps of converting compound of formula (12) as depicted and describedin Scheme 1A below.

Yet another embodiment of the present invention is a method forinhibiting PI3K in a patient by administering to the patient aneffective amount of at least one compound of the present invention (forinstance, a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III)(IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa),(IA-IIIa), (IA-Ib) or (IA-IIb) as defined above).

Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asPI3K) by administering to a patient in need of such treatment aneffective amount of at least one compound of the present invention. Inone embodiment, the compound of the present invention inhibits a proteinkinase (such as PI3K).

Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asPI3K) by administering to a patient in need of such treatment aneffective amount of at least one compound of the present invention, incombination (simultaneously or sequentially) with at least one otheranti-cancer agent. In one embodiment, the compound of formula I), (IA),(IA-I), (IA-II), (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII),(IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb) inhibits a proteinkinase (such as PI3K).

More particularly, the compounds of formula I), (IA), (IA-I), (IA-II),(IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII), (IA-VIII), (IA-Ia),(IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb) and pharmaceutically acceptableesters or salts thereof can be administered for the treatment,prevention and/or amelioration of PI3K and related protein kinasemediated diseases or disorders, including but not limited to, cancer andother proliferative diseases or disorders.

The compounds of the present invention are useful in the treatment of avariety of cancers, including, but not limited to, the following:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   hematopoietic tumors of lymphoid lineage, including leukemia,        acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell        lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins        lymphoma, hairy cell lymphoma and Burkett's lymphoma;    -   hematopoietic tumors of myeloid lineage, including acute and        chronic myelogenous leukemias, myelodysplastic syndrome and        promyelocytic leukemia;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.

Due to the key role of protein kinases in the regulation of cellularproliferation in general, the protein kinase inhibitors of the presentinvention could act as reversible cytostatic agents which may be usefulin the treatment of any disease process which features abnormal cellularproliferation, e.g., benign prostatic hyperplasia, familial adenomatosispolyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis,arthritis, psoriasis, glomerulonephritis, restenosis followingangioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

The compounds of the present invention as modulators of apoptosis areuseful in the treatment of cancer (including but not limited to thosetypes mentioned herein above), viral infections (including but notlimited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of present invention can modulate the level of cellularRNA and DNA synthesis. These agents are therefore useful in thetreatment of viral infections (including but not limited to HIV, humanpapilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).

The compounds of the present invention are useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse. The compounds are alsouseful in inhibiting tumor angiogenesis and metastasis. One embodimentof the invention is a method of inhibiting tumor angiogenesis ormetastasis in a patient in need thereof by administering an effectiveamount of one or more compounds of the present invention.

Another embodiment of the present invention is a method of treating animmune system-related disease (e.g., an autoimmune disease), a diseaseor disorder involving inflammation (e.g., asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, inflammatory bowel disease,glomerulonephritis, neuroinflammatory diseases, multiple sclerosis,uveitis and disorders of the immune system), cancer or otherproliferative disease, a hepatic disease or disorder, a renal disease ordisorder. The method includes administering an effective amount of oneor more compounds of the present invention.

Examples of immune disorders include psoriasis, rheumatoid arthritis,vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis,asthma, inflammatory muscle disease, allergic rhinitis, vaginitis,interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

In one embodiment, the compounds described herein are used asimmunosuppresants to prevent transplant graft rejections, allogeneic orxenogeneic transplantation rejection (organ, bone marrow, stem cells,other cells and tissues), and graft-versus-host disease. In otherembodiments, transplant graft rejections result from tissue or organtransplants. In further embodiments, graft-versus-host disease resultsfrom bone marrow or stem cell transplantation. One embodiment is amethod of preventing or decreasing the risk of transplant graftrejection, allogeneic or xenogeneic transplantation rejection (organ,bone marrow, stem cells, other cells and tissues), or graft-versus-hostdisease by administering an effective amount of one or more compounds ofthe present invention.

The compounds of the present invention are also useful in combination(administered together or sequentially) with known anti-cancertreatments such as radiation therapy or with cytostatic or cytotoxic oranticancer agents, such as for example, but not limited to, DNAinteractive agents, such as cisplatin or doxorubicin; topoisomerase IIinhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11or topotecan; tubulin interacting agents, such as paclitaxel, docetaxelor the epothilones (for example ixabepilone), either naturally occurringor synthetic; hormonal agents, such as tamoxifen; thymidilate synthaseinhibitors, such as 5-fluorouracil; and anti-metabolites, such asmethotrexate, other tyrosine kinase inhibitors such as Iressa andOSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDKinhibitors; SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors andmonoclonal antibodies directed against growth factor receptors such aserbitux (EGF) and herceptin (Her2) and other protein kinase modulatorsas well.

The compounds of the present invention are also useful in combination(administered together or sequentially) with one or more steroidalanti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs)or Immune Selective Anti-Inflammatory Derivatives (ImSAIDs).

The invention further provides a pharmaceutical composition comprisingone or more compounds of the present invention (such as a compoundhaving formula (I), (IA), (IA-I), (IA-II), (IA-III) (IA-IV), (IA-V),(IA-VI), (IA-VII), (IA-VIII), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or(IA-IIb)) together with a pharmaceutically acceptable carrier. Thepharmaceutical composition may further comprise one or more of theactive ingredients identified above, such as other anti-cancer agents.

In one embodiment, the pharmaceutical composition includes atherapeutically effective amount of one or more compounds of formula(I), (IA), (IA-I), (IA-II), (IA-III) (IA-IV), (IA-V), (IA-VI), (IA-VII),(IA-VIII), (IA-Ia), (IA-IIa), (IA-IIIa), (IA-Ib) or (IA-IIb).

Yet another embodiment is a method of treating leukemia in a patient inneed thereof by administering a therapeutically effective amount of acompound of the present invention. For example, the compounds of thepresent invention are effective for treating chronic lymphocyticleukemia (CLL), non-Hodgkin lymphoma (NHL), acute myeloid leukemia(AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), andindolent non-Hodgkin's lymphoma (I-NHL).

Yet another embodiment is a method of treating allergic rhinitis in apatient in need thereof by administering a therapeutically effectiveamount of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following definitions shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term “alkyl”, unless otherwise specified, refers to a straight orbranched hydrocarbon chain radical consisting solely of carbon andhydrogen atoms, containing no unsaturation, having from one to eightcarbon atoms, and which is attached to the rest of the molecule by asingle bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl),n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term“(C₁₋₆)alkyl” refers to an alkyl group as defined above having up to 6carbon atoms.

The term “alkenyl”, unless otherwise specified, refers to an aliphatichydrocarbon group containing a carbon-carbon double bond and which maybe a straight or branched or branched chain having about 2 to about 10carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl),iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. The term“(C₂₋₆)alkenyl” refers to an alkenyl group as defined above having up to6 carbon atoms.

The term “alkynyl”, unless otherwise specified, refers to a straight orbranched chain hydrocarbyl radical having at least one carbon-carbontriple bond, and having in the range of 2 to up to 12 carbon atoms (withradicals having in the range of 2 to up to 10 carbon atoms presentlybeing preferred) e.g., ethynyl, propynyl, and butnyl. The term “(C₂₋₆)alkynyl” refers to an alkynyl group as defined above having up to 6carbon atoms.

The term “alkoxy” unless otherwise specified, denotes an alkyl,cycloalkyl, or cycloalkylalkyl group as defined above attached via anoxygen linkage to the rest of the molecule. The term “substitutedalkoxy” refers to an alkoxy group where the alkyl constituent issubstituted (i.e., —O-(substituted alkyl) wherein the term “substitutedalkyl” is the same as defined above for “alkyl”. For example “alkoxy”refers to the group —O-alkyl, including from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

The term “cycloalkyl”, unless otherwise specified, denotes anon-aromatic mono or multicyclic ring system of about 3 to 12 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Examples of multicyclic cycloalkyl groups include perhydronaphthyl,adamantyl and norbornyl groups, bridged cyclic groups, andsprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term “(C₃₋₈)cycloalkyl” refers to a cycloalkyl group as defined above having up to 8carbon atoms.

The term “cycloalkylalkyl”, unless otherwise specified, refers to acyclic ring-containing radical containing in the range of about 3 up to8 carbon atoms directly attached to an alkyl group which are thenattached to the main structure at any carbon from the alkyl group thatresults in the creation of a stable structure such as cyclopropylmethyl,cyclobutylethyl, and cyclopentylethyl.

The term “cycloalkenyl”, unless otherwise specified, refers to cyclicring-containing radicals containing in the range of about 3 up to 8carbon atoms with at least one carbon-carbon double bond such ascyclopropenyl, cyclobutenyl, and cyclopentenyl. The term“cycloalkenylalkyl” refers to a cycloalkenyl group directly attached toan alkyl group which are then attached to the main structure at anycarbon from the alkyl group that results in the creation of a stablestructure.

The term “aryl”, unless otherwise specified, refers to aromatic radicalshaving in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl,tetrahydronaphthyl, indanyl, and biphenyl.

The term “arylalkyl”, unless otherwise specified, refers to an arylgroup as defined above directly bonded to an alkyl group as definedabove, e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring”, unless otherwise specified, refers to anon-aromatic 3 to 15 member ring radical which consists of carbon atomsand at least one heteroatom selected from nitrogen, phosphorus, oxygenand sulfur. For purposes of this invention, the heterocyclic ringradical may be a mono-, bi-, tri- or tetracyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized. Theheterocyclic ring radical may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablestructure.

The term “heterocyclyl”, unless otherwise specified, refers to aheterocylic ring radical as defined above. The heterocylcyl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure.

The term “heterocyclylalkyl”, unless otherwise specified, refers to aheterocylic ring radical as defined above directly bonded to an alkylgroup. The heterocyclylalkyl radical may be attached to the mainstructure at carbon atom in the alkyl group that results in the creationof a stable structure. Examples of such heterocycloalkyl radicalsinclude, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

The term “heteroaryl”, unless otherwise specified, refers to anoptionally substituted 5 to 14 member aromatic ring having one or moreheteroatoms selected from N, O, and S as ring atoms. The heteroaryl maybe a mono-, bi- or tricyclic ring system. Examples of such “heterocyclicring” or “heteroaryl” radicals include, but are not limited to,oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl,pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl,benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl,benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl,dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl,pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. The term“substituted heteroaryl” also includes ring systems substituted with oneor more oxide. (—O—) substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl”, unless otherwise specified, refers to aheteroaryl ring radical as defined above directly bonded to an alkylgroup. The heteroarylalkyl radical may be attached to the main structureat any carbon atom from alkyl group that results in the creation of astable structure.

The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbonatoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents which may be the same or different and are independentlyselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heteroarylalkyl, substituted or unsubstitutedheterocyclic ring, substituted heterocyclylalkyl ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—, —SO₂NR^(x)R^(y)—, —OR^(x),—OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—, —OC(O)R^(x),—OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, whereinR^(x), R^(y) and R^(z) in each of the above groups can be hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted amino, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,substituted or unsubstituted heterocyclic ring, or substitutedheterocyclylalkyl ring, or any two of R^(x), R^(y) and R^(z) may bejoined to form a substituted or unsubstituted saturated or unsaturated3-10 membered ring, which may optionally include heteroatoms which maybe the same or different and are selected from O, NR^(x) (e.g., R^(x)can be hydrogen or C₁₋₆ alkyl) or S. Substitution or the combinations ofsubstituents envisioned by this invention are preferably those thatresult in the formation of a stable or chemically feasible compound. Theterm stable as used herein refers to the compounds or the structure thatare not substantially altered when subjected to conditions to allow fortheir production, detection and preferably their recovery, purificationand incorporation into a pharmaceutical composition. The substituents inthe aforementioned “substituted” groups cannot be further substituted.For example, when the substituent on “substituted alkyl” is “substitutedaryl”, the substituent on “substituted aryl” cannot be “substitutedalkenyl”.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. For the instance the non-limiting example ofintermediate mixtures include a mixture of isomers in a ratio of 10:90,13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers canbe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention. “Tautomers” arestructurally distinct isomers that interconvert by tautomerization.“Tautomerization” is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order, often the interchange of a single bond with anadjacent double bond. Where tautomerization is possible (e.g. insolution), a chemical equilibrium of tautomers can be reached. Anexample of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconversion ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes. Prodrug design is discussed generally in Hardma, etal. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion isprovided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). To illustrate, prodrugs can be converted into apharmacologically active form through hydrolysis of, for example, anester or amide linkage, thereby introducing or exposing a functionalgroup on the resultant product. The prodrugs can be designed to reactwith an endogenous compound to form a water-soluble conjugate thatfurther enhances the pharmacological properties of the compound, forexample, increased circulatory half-life. Alternatively, prodrugs can bedesigned to undergo covalent modification on a functional group with,for example, glucuronic acid, sulfate, glutathione, amino acids, oracetate. The resulting conjugate can be inactivated and excreted in theurine, or rendered more potent than the parent compound. High molecularweight conjugates also can be excreted into the bile, subjected toenzymatic cleavage, and released back into the circulation, therebyeffectively increasing the biological half-life of the originallyadministered compound.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the general formula RCOOR′.

These prodrugs and esters are intended to be covered within the scope ofthis invention.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ¹³C- or ¹⁴C-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, omithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, alkylsulphates such as Mel and (Me)₂SO₄; non-natural amino acids such asD-isomers or substituted amino acids; guanidine; and substitutedguanidine wherein the substituents are selected from nitro, amino,alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) includes thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

The following abbreviations and terms have the indicated meaningsthroughout: PI3-K=Phosphoinositide 3-kinase; PI=phosphatidylinositol;PDK=Phosphoinositide Dependent Kinase; DNA-PK=Deoxyribose Nucleic AcidDependent Protein Kinase; PTEN=Phosphatase and Tensin homolog deleted onchromosome Ten; PIKK=Phosphoinositide Kinase Like Kinase; AIDS=AcquiredImmuno Deficiency Syndrome; HIV=Human Immunodeficiency Virus; Mel=MethylIodide; POCI₃=Phosphorous Oxychloride; KCNS=Potassium IsoThiocyanate;TLC=Thin Layer Chromatography; MeOH=Methanol; and CHCl₃=Chloroform.

Abbreviations used herein have their conventional meaning within thechemical and biological arts.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment,” “treating,” or “ameliorating” are usedinterchangeably. These terms refers to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient may still be afflicted withthe underlying disorder. For prophylactic benefit, the compositions maybe administered to a patient at risk of developing a particular disease,or to a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “subject” or “patient” refers to an animal, such as a mammal,for example a human. The methods described herein can be useful in bothhuman therapeutics and veterinary applications. In some embodiments, thepatient is a mammal, and in some embodiments, the patient is human.

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or indirect interaction with the target.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes, but is not limited to, any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, one or more suitablediluents, fillers, salts, disintegrants, binders, lubricants, glidants,wetting agents, controlled release matrices, colorants/flavoring,carriers, excipients, buffers, stabilizers, solubilizers, andcombinations thereof. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions of the invention is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

In some embodiments, one or more subject compounds bind specifically toa PI3 kinase or a protein kinase selected from the group consisting ofmTor, DNA-dependent protein kinase (Pubmed protein accession number(PPAN) AAA79184), AbI tyrosine kinase (CAA52387), Bcr-Abl, hemopoieticcell kinase (PPAN CAI19695), Src (PPAN CAA24495), vascular endothelialgrowth factor receptor 2 (PPAN ABB82619), epidermal growth factorreceptor (PPAN AG43241), EPH receptor B4 (PPAN EAL23820), stem cellfactor receptor (PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2(PPAN q02858), fins-related tyrosine kinase 3 (PPAN NP_004110),platelet-derived growth factor receptor alpha (PPAN NP_990080), RET(PPAN CAA73131), and any other related protein kinases, as well as anyfunctional mutants thereof.

In some embodiments, the IC50 of a subject compound for pi 10α, pi 10β,pi 10γ, or pi 10δ is less than about 1 uM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than 1 nM or even lessthan about 0.5 nM. In some embodiments, the IC50 of a subject compoundfor mTor is less than about 1 uM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than 1 nM or even less thanabout 0.5 nM. In some other embodiments, one or more subject compoundsexhibit dual binding specificity and are capable of inhibiting a PI3kinase (e.g., a class i PI3 kinase) as well as a protein kinase (e.g.,mTor) with an IC50 value less than about 1 uM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than 1 nM or evenless than about 0.5 nM.

In some embodiments, the compounds of the present invention exhibit oneor more functional characteristics disclosed herein. For example, one ormore subject compounds bind specifically to a PI3 kinase. In someembodiments, the IC50 of a subject compound for pi 10α, pi 10β1, pi 10γ,or pi 10δ is less than about 1 uM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than about 1 nM, less thanabout 0.5 nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the subject compounds mayselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measuredin an in vitro kinase assay.

In some embodiments, one or more of the subject compound may selectivelyinhibit one or two members of type I or class I phosphatidylinositol3-kinases (PI3-kinase) consisting of PI3-kinase α, PI3-kinase β,PI3-kinase γ, and PI3-kinase δ. In some aspects, some of the subjectcompounds selectively inhibit PI3-kinase α as compared to all other typeI PI3-kinases. In other aspects, some of the subject compoundsselectively inhibit PI3-kinase δ and PI3-kinase γ as compared to therest of the type I PI3-kinases. In yet other aspects, some of thesubject compounds selectively inhibit PI3-kinase α and PI3-kinase β ascompared to the rest of the type 1 PI3-kinases. In still yet some otheraspects, some of the subject compounds selectively inhibit PI3-kinase δand PI3-kinase α as compared to the rest of the type 1 PI3-kinases. Instill yet some other aspects, some of the subject compounds selectivelyinhibit PI3-kinase δ and PI3-kinase β as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase αas compared to the rest of the type I PI3-kinases, or selectivelyinhibit PI3-kinase α and PI3-kinase γ as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase(i as compared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC50) with respect to a given type IPI3-kinase, that is at least at least 10-fold, at least 20-fold, atleast 50-fold, at least 100-fold, at least 1000-fold, or lower, than theinhibitor's IC50 with respect to the rest of the other type IPI3-kinases.

As used herein, the term “PI3-kinase δ selective inhibitor” generallyrefers to a compound that inhibits the activity of the PI3-kinase δisozyme more effectively than other isozymes of the PI3K family. API3-kinase δ selective inhibitor compound is therefore more selectivefor PI3-kinase δ than conventional PI3K inhibitors such as wortmanninand LY294002, which are “nonselective PI3K inhibitors.”

Inhibition of PI3-kinase: may be of therapeutic benefit in treatment ofvarious conditions, e.g., conditions characterized by an inflammatoryresponse including but not limited to autoimmune diseases, allergicdiseases, and arthritic diseases. Importantly, inhibition of PI3-kinaseδ function does not appear to affect biological functions such asviability and fertility.

“Inflammatory response” as used herein is characterized by redness,heat, swelling and pain (i.e., inflammation) and typically involvestissue injury or destruction. An inflammatory response is usually alocalized, protective response elicited by injury or destruction oftissues, which serves to destroy, dilute or wall off (sequester) boththe injurious agent and the injured tissue. Inflammatory responses arenotably associated with the influx of leukocytes and/or leukocyte (e.g.,neutrophil) chemotaxis. Inflammatory responses may result from infectionwith pathogenic organisms and viruses, noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune diseases. Inflammatoryresponses amenable to treatment with the methods and compounds accordingto the invention encompass conditions associated with reactions of thespecific defense system as well as conditions associated with reactionsof the non-specific defense system.

The therapeutic methods of the invention include methods for theamelioration of conditions associated with inflammatory cell activation.“Inflammatory cell activation” refers to the induction by a stimulus(including but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including but not limited to,major histocompatibility antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (polymorphonuclear leukocytesincluding neutrophils, basophils, and eosinophils) mast cells, dendriticcells, Langerhans cells, and endothelial cells). It will be appreciatedby persons skilled in the art that the activation of one or acombination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory condition.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents. “Transplant rejection” as usedherein refers-to any immune response directed against grafted tissue(including organs or cells (e.g., bone marrow), characterized by a lossof function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia). “Allergic disease” as used hereinrefers to any symptoms, tissue damage, or loss of tissue functionresulting from allergy. “Arthritic disease” as used herein refers to anydisease that is characterized by inflammatory lesions of the jointsattributable to a variety of etiologies. “Dermatitis” as used hereinrefers to any of a large family of diseases of the skin that arecharacterized by inflammation of the skin attributable to a variety ofetiologies.

As previously described, the term “PI3-kinase δ selective inhibitor”generally refers to a compound that inhibits the activity of thePI3-kinase δ isozyme more effectively than other isozymes of the PI3Kfamily. The relative efficacies of compounds as inhibitors of an enzymeactivity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC50”. IC50 determinations can beaccomplished using conventional techniques known in the art. In general,an IC50 can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC50 value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC90, etc.

Accordingly, a PI3-kinase δ selective inhibitor alternatively can beunderstood to refer to a compound that exhibits a 50% inhibitoryconcentration (IC50) with respect to PI3-kinase δ, that is at least10-fold, in another aspect at least 20-fold, and in another aspect atleast 30-fold, lower than the IC50 value with respect to any or all ofthe other class I PI3K family members. In an alternative embodiment ofthe invention, the term PI3-kinase δ selective inhibitor can beunderstood to refer to a compound that exhibits an IC50 with respect toP3-kinase δ that is at least 50-fold, in another aspect at least100-fold, in an additional aspect at least 200-fold, and in yet anotheraspect at least 500-fold, lower than the IC50 with respect to any or allof the other PI3K class I family members. A PI3-kinase δ selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3-kinase δ activity, as described above.

The methods of the invention may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human or in a subject's body. In this context, the methods ofthe invention may be used therapeutically or prophylactically in anindividual. “Ex vivo” or “In vitro” means outside of a livingindividual. Examples of ex vivo cell populations include in vitro cellcultures and biological samples including but not limited to fluid ortissue samples obtained from individuals. Such samples may be obtainedby methods known in the art. Exemplary biological fluid samples includeblood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samplesinclude tumors and biopsies thereof. In this context, the invention maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the invention may be used ex vivo orin vitro to determine the optimal schedule and/or dosing ofadministration of a PI3-kinase δ selective inhibitor for a givenindication, cell type, individual, and other parameters. Informationgleaned from such use may be used for experimental or diagnosticpurposes or in the clinic to set protocols for in vivo treatment. Otherex vivo uses for which the invention may be suited are described belowor will become apparent to those skilled in the art.

Pharmaceutical Composition

The invention provides a pharmaceutical composition comprising one ormore compounds of the present invention. The pharmaceutical compositionmay include one or more additional active ingredients as describedherein. The pharmaceutical composition may be administered for any ofthe disorders described herein

In some embodiments, the invention provides pharmaceutical compositionsfor treating diseases or conditions related to an undesirable,over-active, harmful or deleterious immune response in a mammal. Suchundesirable immune response can be associated with or result in, e.g.,asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis,auto-immune diseases, rhuematoid arthritis, graft versus host disease,and lupus erythematosus. The pharmaceutical compositions of the presentinvention can be used to treat other respiratory diseases including butnot limited to diseases affecting the lobes of lung, pleural cavity,bronchial tubes, trachea, upper respiratory tract, or the nerves andmuscle for breathing.

In some embodiments, the invention provides pharmaceutical compositionsfor the treatment of disorders such as hyperproliferative disorderincluding but not limited to cancer such as acute myeloid leukemia,thymus, brain, lung, squamous cell, skin, eye, retinoblastoma,intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric,stomach, pancreatic, bladder, breast, cervical, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, esophageal, testicular,gynecological, thyroid, CNS, PNS, AIDS related (e.g. Lymphoma andKaposi's Sarcoma) or Viral-Induced cancer. In some embodiments, thepharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatichypertrophy (BPH)).

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal which can manifestas tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis or kidney disease (includingproliferative glomerulonephritis and diabetes-induced renal disease) orpain in a mammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal.

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, or prodrug thereof. Where desired, the pharmaceuticalcompositions contain a compound of the present invention as the activeingredient or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, such as inert solid diluents and fillers, diluents, includingsterile aqueous solution and various organic solvents, permeationenhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the subject compounds and other agent(s) may be mixed into a preparationor both components may be formulated into separate preparations to usethem in combination separately or at the same time.

Methods include administration of an inhibitor by itself, or incombination as described herein, and in each case optionally includingone or more suitable diluents, fillers, salts, disintegrants, binders,lubricants, glidants, wetting agents, controlled release matrices,colorants/flavoring, carriers, excipients, buffers, stabilizers,solubilizers, and combinations thereof.

Preparations of various pharmaceutical compositions are known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all ofwhich are incorporated by reference herein in their entirety.

The compounds or pharmaceutical composition of the present invention canbe administered by any route that enables delivery of the compounds tothe site of action, such asoral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topicaladministration (e.g. transdermal application), rectal administration,via local delivery by catheter or stent or through inhalation. Thecompounds can also be administered intraadiposally or intrathecally.

The compositions can be administered in solid, semi-solid, liquid orgaseous form, or may be in dried powder, such as lyophilized form. Thepharmaceutical compositions can be packaged in forms convenient fordelivery, including, for example, solid dosage forms such as capsules,sachets, cachets, gelatins, papers, tablets, capsules, suppositories,pellets, pills, troches, and lozenges. The type of packaging willgenerally depend on the desired route of administration. Implantablesustained release formulations are also contemplated, as are transdermalformulations.

Routes of Administration

In the methods according to the invention, the inhibitor compounds maybe administered by various routes. For example, pharmaceuticalcompositions may be for injection, or for oral, nasal, transdermal orother forms of administration, including, e.g., by intravenous,intradermal, intramuscular, intramammary, intraperitoneal, intrathecal,intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) orsubcutaneous injection (including depot administration for long termrelease e.g., embedded-under the-splenic capsule, brain, or in thecornea); by sublingual, anal, or vaginal administration, or by surgicalimplantation, e.g., embedded under the splenic capsule, brain, or in thecornea. The treatment may consist of a single dose or a plurality ofdoses over a period of time. In general, the methods of the inventioninvolve administering effective amounts of a modulator of the inventiontogether with one or more pharmaceutically acceptable diluents,preservatives, solubilizers, emulsifiers, adjuvants and/or carriers, asdescribed above.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, and adjuvants.

In one aspect, the invention provides methods for oral administration ofa pharmaceutical composition of the invention. Oral solid dosage formsare described generally in Remington's Pharmaceutical Sciences, supra atChapter 89. Solid dosage forms include tablets, capsules, pills, trochesor lozenges, and cachets or pellets. Also, liposomal or proteinoidencapsulation may be used to formulate the compositions (as, forexample, proteinoid microspheres reported in U.S. Pat. No. 4,925,673).Liposomal encapsulation may include liposomes that are derivatized withvarious polymers (e.g., U.S. Pat. No. 5,013,556). The formulation mayinclude a compound of the invention and inert ingredients which protectagainst degradation in the stomach and which permit release of thebiologically active material in the intestine.

Toxicity and therapeutic efficacy of the PI3-kinase δ selectivecompounds can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50 (the dosetherapeutically effective in 50% of the population). Additionally, thisinformation can be determined in cell cultures or experimental animalsadditionally treated with other therapies including but not limited toradiation, chemotherapeutic agents, photodynamic therapies,radiofrequency ablation, anti-angiogenic agents, and combinationsthereof.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In practice of the methods of the invention, the pharmaceuticalcompositions are generally provided in doses ranging from 1 pgcompound/kg body weight to 1000 mg/kg, 0.1 mg/kg to 100 mg/kg, 0.1 mg/kgto 50 mg/kg, and 1 to 20 mg/kg, given in daily doses or in equivalentdoses at longer or shorter intervals, e.g., every other day, twiceweekly, weekly, or twice or three times daily. The inhibitorcompositions may be administered by an initial bolus followed by acontinuous infusion to maintain therapeutic circulating levels of drugproduct. Those of ordinary skill in the art will readily optimizeeffective dosages and administration regimens as determined by goodmedical practice and the clinical condition of the individual to betreated. The frequency of dosing will depend on the pharmacokineticparameters of the agents and the route of administration. The optimalpharmaceutical formulation will be determined by one skilled in the artdepending upon the route of administration and desired dosage [see, forexample, Remington's Pharmaceutical Sciences, pp. 1435-1712, thedisclosure of which is hereby incorporated by reference]. Suchformulations may influence the physical state, stability, rate of invivo release, and rate of in vivo clearance of the administered agents.Depending on the route of administration, a suitable dose may becalculated according to body weight, body surface area or organ size.Further refinement of the calculations necessary to determine theappropriate dosage for treatment involving each of the above mentionedformulations is routinely made by those of ordinary skill in the artwithout undue experimentation, especially in light of the dosageinformation and assays disclosed herein, as well as the pharmacokineticdata observed in human clinical trials. Appropriate dosages may beascertained by using established assays for determining blood leveldosages in conjunction with an appropriate physician considering variousfactors which modify the action of drugs, e.g., the drug's specificactivity, the severity of the indication, and the responsiveness of theindividual, the age, condition, body weight, sex and diet of theindividual, the time of administration and other clinical factors. Asstudies are conducted, further information will emerge regarding theappropriate dosage levels and duration of treatment for various diseasesand conditions capable of being treated with the methods of theinvention.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The inhibitors of the invention may be covalently or noncovalentlyassociated with a carrier molecule including but not limited to a linearpolymer (e.g., polyethylene glycol, polylysine, dextran, etc.), abranched-chain polymer (see U.S. Pat. Nos. 4,289,872 and 5,229,490; PCTPublication No. WO 93/21259), a lipid, a cholesterol group (such as asteroid), or a carbohydrate or oligosaccharide. Specific examples ofcarriers for use in the pharmaceutical compositions of the inventioninclude carbohydrate-based polymers such as trehalose, mannitol,xylitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran,cellulose, and cellulose derivatives. Also, the use of liposomes,microcapsules or microspheres, inclusion complexes, or other types ofcarriers is contemplated.

Other carriers include one or more water soluble polymer attachmentssuch as polyoxyethylene glycol, or polypropylene glycol as describedU.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and4,179,337. Still other useful carrier polymers known in the art includemonomethoxy-polyethylene glycol, poly-(N-vinyl pyrrolidone)-polyethyleneglycol, propylene glycol homopolymers, a polypropylene oxidelethyleneoxide co-polymer, polyoxyethylated polyols (e.g., glycerol) andpolyvinyl alcohol, as well as mixtures of these polymers.

Derivitization with bifunctional agents is useful for cross-linking acompound of the invention to a support matrix or to a carrier. One suchcarrier is polyethylene glycol (PEG). The PEG group may be of anyconvenient molecular weight and may be straight chain or branched. Theaverage molecular weight of the PEG can range from about 2 kDa to about100 kDa, in another aspect from about 5 kDa to about 50 kDa, and in afurther aspect from about 5 kDa to about 10 kDa. The PEG groups willgenerally be attached to the compounds of the invention via acylation,reductive alkylation, Michael addition, thiol alkylation or otherchemoselective conjugation/ligation methods through a reactive group onthe PEG moiety (e.g., an aldehyde, amino, ester, thiol, ci-haloacetyl,maleimido or hydrazino group) to a reactive group on the targetinhibitor compound (e.g., an aldehyde, amino, ester, thiol,a-haloacetyl, maleimido or hydrazino group). Cross-linking agents caninclude, e.g., esters with 4-azidosalicylic acid, homobifunctionalimidoesters, including disuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate), and bifunctional maleimides such asbis-N-maleimido-1,8-octane. Derivatizing agents such asmethyl-3-[(p-azidophenyl)dithiolpropioimidate yield photoactivatableintermediates that are capable of forming crosslinks in the presence oflight. Alternatively, reactive water-insoluble matrices such as cyanogenbromide-activated carbohydrates and the reactive substrates described inU.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537;and 4,330,440 may be employed for inhibitor immobilization.

Method of Treatment

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to diseases associated withmalfunctioning of one or more types of PI3 kinase. A detaileddescription of conditions and disorders mediated by pi 106 kinaseactivity is set forth in WO 2001/81346 and US 2005/043239, both of whichare incorporated herein by reference in their entireties for allpurposes.

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof.

The disorders, diseases, or conditions treatable with a compoundprovided herein, include, but are not limited to,

-   -   inflammatory or allergic diseases, including systemic        anaphylaxis and hypersensitivity disorders, atopic dermatitis,        urticaria, drug allergies, insect sting allergies, food        allergies (including celiac disease and the like), anaphylaxis,        serum sickness, drug reactions, insect venom allergies,        hypersensitivity pneumonitis, angioedema, erythema multiforme,        Stevens-Johnson syndrome, atopic keratoconjunctivitis, venereal        keratoconjunctivitis, giant papillary conjunctivitis, and        mastocytosis;    -   inflammatory bowel diseases, including Crohn's disease,        ulcerative colitis, ileitis, enteritis, and necrotizing        enterocolitis;    -   vasculitis, and Behcet's syndrome;    -   psoriasis and inflammatory dermatoses, including dermatitis,        eczema, allergic contact dermatitis, viral cutaneous pathologies        including those derived from human papillomavirus, HIV or RLV        infection, bacterial, flugal, and other parasital cutaneous        pathologies, and cutaneous lupus erythematosus;    -   asthma and respiratory allergic diseases, including allergic        asthma, exercise induced asthma, allergic rhinitis, otitis        media, hypersensitivity lung diseases, chronic obstructive        pulmonary disease and other respiratory problems;    -   autoimmune diseases and inflammatory conditions, including but        are not limited to acute disseminated encephalomyelitis (ADEEM),        Addison's disease, antiphospholipid antibody syndrome (APS),        plat anemia, autoimmune hepatitis, coeliac disease, Crohn's        disease, Diabetes mellitus (type 0), Goodpasture's syndrome,        Graves' disease, Guillain-Barre syndrome (GBS), Reynaud's        syndrome, Hashimoto's disease, lupus erythematosus, systemic        lupus erythematosus (SLE), multiple sclerosis, myasthenia        gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis,        Ord's thyroiditis, oemphigus, polyarthritis, primary biliary        cirrhosis, psoriasis, rheumatoid arthritis, psoriatic arthritis,        gouty arthritis, spondylitis, reactive arthritis, chronic or        acute glomerulonephritis, lupus nephritis, Reiter's syndrome,        Takayasu's arteritis, temporal arteritis (also known as “giant        cell arteritis”), warn autoimmune hemolytic anemia, Wegener's        granulomatosis, alopecia universalis, Chagas' disease, chronic        fatigue syndrome, dysautonomia, endometriosis, hidradenitis        suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis,        scleroderma, ulcerative colitis, connective tissue disease,        autoimmune pulmonary inflammation, autoimmune thyroiditis,        autoimmune inflammatory eye disease, vitiligo, and vulvodynia.        Other disorders include bone-resorption disorders and        thrombosis;    -   tissue or organ transplant rejection disorders including but not        limited to graft rejection (including allograft rejection and        graft-v-host disease (GVHD)), e.g., skin graft rejection, solid        organ transplant rejection, bone marrow transplant rejection;    -   fever;    -   cardiovascular disorders, including acute heart failure,        hypotension, hypertension, angina pectoris, myocardial        infarction, cardiomyopathy, congestive heart failure,        atherosclerosis, coronary artery disease, restenosis, and        vascular stenosis;    -   cerebrovascular disorders, including traumatic brain injury,        stroke, ischemic reperfusion injury and aneurysm;    -   cancers of the breast, skin, prostate, cervix, uterus, ovary,        testes, bladder, lung, liver, larynx, oral cavity, colon and        gastrointestinal tract (e.g., esophagus, stomach, pancreas),        brain, thyroid, blood, and lymphatic system;    -   fibrosis, connective tissue disease, and sarcoidosis;    -   genital and reproductive conditions, including erectile        dysfunction;    -   gastrointestinal disorders, including gastritis, ulcers, nausea,        pancreatitis, and vomiting;    -   neurologic disorders, including Alzheimer's disease;    -   sleep disorders, including insomnia, narcolepsy, sleep apnea        syndrome, and Pickwick Syndrome;    -   pain, myalgias due to infection;    -   renal disorders;    -   ocular disorders, including glaucoma;    -   infectious diseases, including HIV;    -   sepsis; septic shock; endotoxic shock; gram negative sepsis;        gram positive sepsis;

toxic shock syndrome; multiple organ injury syndrome secondary tosepticemia, trauma, or hemorrhage;

-   -   pulmonary or respiratory conditions including but not limited to        asthma, chronic bronchitis, allergic rhinitis, adult respiratory        distress syndrome (ARDS), severe acute respiratory syndrome        (SARS), chronic pulmonary inflammatory diseases (e.g., chronic        obstructive pulmonary disease), silicosis, pulmonary        sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia,        bronchiectasis, hereditary emphysema, and pulmonary oxygen        toxicity;    -   ischemic-reperfusion injury, e.g., of the myocardium, brain, or        extremities;    -   fibrosis including but not limited to cystic fibrosis; keloid        formation or scar tissue formation;    -   central or peripheral nervous system inflammatory conditions        including but not limited to meningitis (e.g., acute purulent        meningitis), encephalitis, and brain or spinal cord injury due        to minor trauma;    -   Sjorgren's syndrome; diseases involving leukocyte diapedesis;        alcoholic hepatitis; bacterial pneumonia; community acquired        pneumonia (CAP); Pneumocystis carinii pneumonia (PCP);        antigen-antibody complex mediated diseases; hypovolemic shock;        acute and delayed hypersensitivity; disease states due to        leukocyte dyscrasia and metastasis; thermal injury; granulocyte        transfusion associated syndromes; cytokine-induced toxicity;        stroke; pancreatitis; myocardial infarction, respiratory        syncytial virus (RSV) infection; and spinal cord injury.

In certain embodiments, the cancer or cancers treatable with the methodsprovided herein includes, but is or are not limited to,

-   -   leukemias, including, but not limited to, acute leukemia, acute        lymphocytic leukemia, acute myelocytic leukemias such as        myeloblasts, promyelocyte, myelomonocytic, monocytic,        erythroleukemia leukemias and myelodysplastic syndrome or a        symptom thereof (such as anemia, thrombocytopenia, neutropenia,        bicytopenia or pancytopenia), refractory anemia (RA), RA with        ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB        in transformation (RAEB-T), preleukemia, and chronic        myelomonocytic leukemia (CMML);    -   chronic leukemias, including, but not limited to, chronic        myelocytic (granulocytic) leukemia, chronic lymphocytic        leukemia, and hairy cell leukemia;    -   polycythemia vera;    -   lymphomas, including, but not limited to, Hodgkin's disease and        non-Hodgkin's disease;    -   multiple myelomas, including, but not limited to, smoldering        multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma,        plasma cell leukemia, solitary plasmacytoma, and extramedullary        plasmacytoma;    -   Waldenstrom's macroglobulinemia;    -   monoclonal gammopathy of undetermined significance;    -   benign monoclonal gammopathy;    -   heavy chain disease;    -   bone and connective tissue sarcomas, including, but not limited        to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,        malignant giant cell tumor, fibrosarcoma of bone, chordoma,        periosteal sarcoma, soft-tissue sarcomas, angiosarcoma        (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma,        leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic        cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma;    -   brain tumors, including, but not limited to, glioma,        astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,        nonglial tumor, acoustic neurinoma, craniopharyngioma,        medulloblastoma, meningioma, pineocytoma, pineoblastoma, and        primary brain lymphoma;    -   breast cancer, including, but not limited to, adenocarcinoma,        lobular (small cell) carcinoma, intraductal carcinoma, medullary        breast cancer, mucinous breast cancer, tubular breast cancer,        papillary breast cancer, primary cancers, Paget's disease, and        inflammatory breast cancer;    -   adrenal cancer, including, but not limited to, pheochromocytom        and adrenocortical carcinoma;    -   thyroid cancer, including, but not limited to, papillary or        follicular thyroid cancer, medullary thyroid cancer, and        anaplastic thyroid cancer;    -   pancreatic cancer, including, but not limited to, insulinoma,        gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor,        and carcinoid or islet cell tumor;    -   pituitary cancer, including, but limited to, Cushing's disease,        prolactin-secreting tumor, acromegaly, and diabetes insipidus;    -   eye cancer, including, but not limited, to ocular melanoma such        as iris melanoma, choroidal melanoma, and cilliary body        melanoma, and retinoblastoma;    -   vaginal cancer, including, but not limited to, squamous cell        carcinoma, adenocarcinoma, and melanoma;    -   vulvar cancer, including, but not limited to, squamous cell        carcinoma, melanoma, adenocarcinoma, basal cell carcinoma,        sarcoma, and Paget's disease;    -   cervical cancers, including, but not limited to, squamous cell        carcinoma, and adenocarcinoma;    -   uterine cancer, including, but not limited to, endometrial        carcinoma and uterine sarcoma;    -   ovarian cancer, including, but not limited to, ovarian        epithelial carcinoma, borderline tumor, germ cell tumor, and        stromal tumor;    -   esophageal cancer, including, but not limited to, squamous        cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid        carcinoma, adenosquamous carcinoma, sarcoma, melanoma,        plasmacytoma, verrucous carcinoma, and oat cell (small cell)        carcinoma;    -   stomach cancer, including, but not limited to, adenocarcinoma,        fungating (polypoid), ulcerating, superficial spreading,        diffusely spreading, malignant lymphoma, liposarcoma,        fibrosarcoma, and carcinosarcoma;    -   colon cancer;    -   rectal cancer;    -   liver cancer, including, but not limited to, hepatocellular        carcinoma and hepatoblastoma;    -   gallbladder cancer, including, but not limited to,        adenocarcinoma;    -   cholangiocarcinomas, including, but not limited to, pappillary,        nodular, and diffuse;    -   lung cancer, including, but not limited to, non-small cell lung        cancer, squamous cell carcinoma (epidermoid carcinoma),        adenocarcinoma, large-cell carcinoma, and small-cell lung        cancer;    -   testicular cancer, including, but not limited to, germinal        tumor, seminoma, anaplastic, classic (typical), spermatocytic,        nonseminoma, embryonal carcinoma, teratoma carcinoma, and        choriocarcinoma (yolk-sac tumor);    -   prostate cancer, including, but not limited to, adenocarcinoma,        leiomyosarcoma, and rhabdomyosarcoma;    -   penal cancer;    -   oral cancer, including, but not limited to, squamous cell        carcinoma;    -   basal cancer;    -   salivary gland cancer, including, but not limited to,        adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic        carcinoma;    -   pharynx cancer, including, but not limited to, squamous cell        cancer and verrucous;    -   skin cancer, including, but not limited to, basal cell        carcinoma, squamous cell carcinoma and melanoma, superficial        spreading melanoma, nodular melanoma, lentigo malignant        melanoma, and acral lentiginous melanoma;    -   kidney cancer, including, but not limited to, renal cell cancer,        adenocarcinoma,    -   hypernephroma, fibrosarcoma, and transitional cell cancer (renal        pelvis and/or uterer);    -   Wilms' tumor;    -   bladder cancer, including, but not limited to, transitional cell        carcinoma, squamous cell cancer, adenocarcinoma, and        carcinosarcoma; and other cancer, including, not limited to,        myxosarcoma, osteogenic sarcoma, endotheliosarcoma,        lymphangio-endotheliosarcoma, mesothelioma, synovioma,        hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,        bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland        carcinoma, papillary carcinoma, and papillary adenocarcinomas        See Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott        Co., Philadelphia and Murphy et al., 1997, Informed Decisions:        The Complete Book of Cancer Diagnosis, Treatment, and Recovery,        Viking Penguin, Penguin Books U.S.A., Inc., United States of        America.

It will be appreciated that the treatment methods of the invention areuseful in the fields of human medicine and veterinary medicine. Thus,the individual to be treated may be a mammal, preferably human, or otheranimals. For veterinary purposes, individuals include but are notlimited to farm animals including cows, sheep, pigs, horses, and goats;

companion animals such as dogs and cats; exotic and/or zoo animals;laboratory animals including mice, rats, rabbits, guinea pigs, andhamsters; and poultry such as chickens, turkeys, ducks, and geese.

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g. a mammal) atherapeutically effective amount of one or more compounds of the presentinvention that selectively inhibit PI3K-δ and/or PI3K-γ as compared toall other type I PI3 kinases. Such selective inhibition of PI3K-δ and/orPI3K-γ may be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δmay inhibit inflammatory responses associated with inflammatorydiseases, autoimmune disease, or diseases related to an undesirableimmune response including but not limited to asthma, emphysema, allergy,dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, orgraft versus host disease. Selective inhibition of POK-δ may furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomittant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Selective inhibition of bothPI3K-δ and PI3K-γ may be advantageous for inhibiting the inflammatoryresponse in the subject to a greater degree than that would be providedfor by inhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. Inone aspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rhuematoid arthritis including butnot limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments, the present invention provides methods of usingthe compounds or pharmaceutical compositions to treat respiratorydiseases including but not limited to diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein may be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, thymus, brain, lung,squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oralcavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e. g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof. In some embodiments,said method is for treating a disease selected from the group consistingof tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, patients that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct;

bladder cancer such as a transitional cell carcinoma in urinary bladder,urothelial carcinomas (transitional cell carcinomas), tumors in theurothelial cells that line the bladder, squamous cell carcinomas,adenocarcinomas, and small cell cancers; leukemia such as acute myeloidleukemia (AML), acute lymphocytic leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia(CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bonecancer; lung cancer such as non-small cell lung cancer (NSCLC), which isdivided into squamous cell carcinomas, adenocarcinomas, and large cellundifferentiated carcinomas, and small cell lung cancer; skin cancersuch as basal cell carcinoma, melanoma, squamous cell carcinoma andactinic keratosis, which is a skin condition that sometimes developsinto squamous cell carcinoma; eye retinoblastoma; cutaneous orintraocular (eye) melanoma; primary liver cancer (cancer that begins inthe liver); kidney cancer; thyroid cancer such as papillary, follicular,medullary and anaplastic; AIDS-related lymphoma such as diffuse largeB-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleavedcell lymphoma; Kaposi's Sarcoma; viral-induced cancers includinghepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellularcarcinoma; human lymphotropic virus-type 1 (HTLV-I) and adult T-cellleukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer;central nervous system cancers (CNS) such as primary brain tumor, whichincludes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastomamultiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma,Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancerssuch as acoustic neuromas and malignant peripheral nerve sheath tumor(MPNST) including neurofibromas and schwannomas, malignant fibrouscytoma, malignant fibrous histiocytoma, malignant meningioma, malignantmesothelioma, and malignant mixed Mvllerian tumor; oral cavity andoropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer,nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such aslymphomas, gastric stromal tumors, and carcinoid tumors; testicularcancer such as germ cell tumors (GCTs), which include seminomas andnonseminomas, and gonadal stromal tumors, which include Leydig celltumors and Sertoli cell tumors; thymus cancer such as to thymomas,thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids orcarcinoid tumors; rectal cancer; and colon cancer.

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barre syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditiSjOstheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis, chagas¹ disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. Examples of cardiovascular conditions include,but are not limited to, atherosclerosis, restenosis, vascular occlusionand carotid obstructive disease.

In another aspect, the present invention provides methods of disruptingthe function of a leukocyte or disrupting a function of an osteoclast.The method includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more of the subjectcompounds or pharmaceutical compositions to the eye of a subject.

The invention further provides methods of modulating kinase activity bycontacting a kinase with an amount of a compound of the inventionsufficient to modulate the activity of the kinase. Modulate can beinhibiting or activating kinase activity. In some embodiments, theinvention provides methods of inhibiting kinase activity by contacting akinase with an amount of a compound of the invention sufficient toinhibit the activity of the kinase. In some embodiments, the inventionprovides methods of inhibiting kinase activity in a solution bycontacting said solution with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said solution. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in a cell by contacting said cell with an amount of a compoundof the invention sufficient to inhibit the activity of the kinase insaid cell. In some embodiments, the invention provides methods ofinhibiting kinase activity in a tissue by contacting said tissue with anamount of a compound of the invention sufficient to inhibit the activityof the kinase in said tissue. In some embodiments, the inventionprovides methods of inhibiting kinase activity in an organism bycontacting said organism with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said organism. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in an animal by contacting said animal with an amount of acompound of the invention sufficient to inhibit the activity of thekinase in said animal. In some embodiments, the invention providesmethods of inhibiting kinase activity in a mammal by contacting saidmammal with an amount of a compound of the invention sufficient toinhibit the activity of the kinase in said mammal. In some embodiments,the invention provides methods of inhibiting kinase activity in a humanby contacting said human with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said human. In someembodiments, the % of kinase activity after contacting a kinase with acompound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 95, or 99% of the kinase activity in the absence of saidcontacting step.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from the group consisting ofPI3 kinase including different isoforms such as PI3 kinase α, PI3 kinaseR, PI3 kinase γ, PI3 kinase δ; DNA-PK; mTor; AbI, VEGFR, Ephrin receptorB4 (EphB4); TEK receptor tyrosine kinase (HE2); FMS-related tyrosinekinase 3 (FLT-3); Platelet derived growth factor receptor (PDGFR); RET;ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR);KIT; Inulsin Receptor (IR) and IGFR.

The invention further provides methods of modulating PI3 kinase activityby contacting a PI3 kinase with an amount of a compound of the inventionsufficient to modulate the activity of the PI3 kinase. Modulate can beinhibiting or activating PI3 kinase activity. In some embodiments, theinvention provides methods of inhibiting PI3 kinase activity bycontacting a PI3 kinase with an amount of a compound of the inventionsufficient to inhibit the activity of the PI3 kinase. In someembodiments, the invention provides methods of inhibiting PI3 kinaseactivity. Such inhibition can take place in solution, in a cellexpressing one or more PI3 kinases, in a tissue comprising a cellexpressing one or more PI3 kinases, or in an organism expressing one ormore PI3 kinases. In some embodiments, the invention provides methods ofinhibiting PI3 kinase activity in an animal (including mammal such ashumans) by contacting said animal with an amount of a compound of theinvention sufficient to inhibit the activity of the PI3 kinase in saidanimal.

The ability of the compounds of the invention to treat arthritis can bedemonstrated in a murine collagen-induced arthritis model [Kakimoto, etal., Cell. Immunol., 142:326-337 (1992)], in a rat collagen-inducedarthritis model [Knoerzer, et al., Toxicol. Pathol., 25:13-19-(1997)],in a rat adjuvant arthritis model [Halloran, et al., Arthritis Rheum.,39:810-819 (1996)], in a rat streptococcal cell wall-induced arthritismodel [Schimmer, et al., J. Immunol., 160:1466-1477 (1998)], or in aSCID-mouse human rheumatoid arthritis model [Oppenheimer-Marks, et al.,J. Clin. Invest., 101: 1261-1272(1998)].

The ability of the compounds of the invention to treat Lyme arthritiscan be demonstrated according to the method of Gross, et al., Science,218:703-706, (1998).

The ability of the compounds of the invention to treat asthma can bedemonstrated in a murine allergic asthma model according to the methodof Wegner, et al., Science, 247:456-459 (1990), or in a murinenon-allergic asthma model according to the method of Bloemen, et al, Am.J. Respir. Crit. Care Med., 153:521-529 (1996).

The ability of the compounds of the invention to treat inflammatory lunginjury can be demonstrated in a murine oxygen-induced lung injury modelaccording to the method of Wegner, et al., Lung, 170:267-279 (1992), ina murine immune complex-induced lung injury model according to themethod of Mulligan, et al., J. Immunol., 154:1350-1363 (1995), or in amurine acid-induced lung injury model according to the method of Nagase,et al., Am. J. Respir. Crit. Care Med., 154:504-510(1996).

The ability of the compounds of the invention to treat inflammatorybowel disease can be demonstrated in a murine chemical-induced colitismodel according to the method of Bennett, et al., J. Pharmacol. Exp.Ther., 280:988-1000 (1997).

The ability of the compounds of the invention to treat autoimmunediabetes can be demonstrated in an NOD mouse model according to themethod of Hasagawa, et al., Int. Immunol., 6:831-838 (1994), or in amurine streptozotocin-induced diabetes model according to the method ofHerrold, et al., Cell Immunol., 157:489-500 (1994).

The ability of the compounds of the invention to treat inflammatoryliver injury can be demonstrated in a murine liver injury modelaccording to the method of Tanaka, et al., J. Immunol., 151:5088-5095(1993).

The ability of the compounds of the invention to treat inflammatoryglomerular injury can be demonstrated in a rat nephrotoxic serumnephritis model according to the method of Kawasaki, et al., J.Immunol., 150: 1074-1083 (1993).

The ability of the compounds of the invention to treat radiation-inducedenteritis can be demonstrated in a rat abdominal irradiation modelaccording to the method of Panes, et al., Gastroenterology,108:1761-1769 (1995).

The ability of the PI3K delta selective inhibitors to treat radiationpneumonitis can be demonstrated in a murine pulmonary irradiation modelaccording to the method of Hallahan, et al., Proc. Natl. Acad. Sci(USA), 94:6432-6437 (1997).

The ability of the compounds of the invention to treat reperfusioninjury can be demonstrated in the isolated heart according to the methodof Tamiya, et al., Immunopharmacology, 29:53-63 (1995), or in theanesthetized dog according to the model of Hartman, et al., Cardiovasc.Res., 30:47-54 (1995).

The ability of the compounds of the invention to treat pulmonaryreperfusion injury can be demonstrated in a rat lung allograftreperfusion injury model according to the method of DeMeester, et al.,Transplantation, 62:1477-1485 (1996), or in a rabbit pulmonary edemamodel according to the method of Horgan, et al., Am. J. Physiol.,261:H1578-H1584 (1991).

The ability of the compounds of the invention to treat stroke can bedemonstrated in a rabbit cerebral embolism stroke model according to themethod of Bowes, et al., Exp. Neurol., 119:215-219 (1993), in a ratmiddle cerebral artery ischemia-reperfusion model according to themethod of Chopp, et al., Stroke, 25:869-875 (1994), or in a rabbitreversible spinal cord ischemia model according to the method of Clark,et al., Neurosurg., 75:623-627 (1991).

The ability of the compounds of the invention to treat cerebralvasospasm can be demonstrated in a rat experimental vasospasm modelaccording to the method of Oshiro, et al., Stroke, 28:2031-2038 (1997).

The ability of the compounds of the invention to treat peripheral arteryocclusion can be demonstrated in a rat skeletal muscleischemia/reperfusion model according to the method of Gute, et al., Mol.Cell Biochem., 179:169-187 (1998).

The ability of the compounds of the invention to treat graft rejectioncan be demonstrated in a murine cardiac allograft rejection modelaccording to the method of Isobe, et al., Science, 255:1125-1127 (1992),in a murine thyroid gland kidney capsule model according to the methodof Talento, et al., Transplantation, 55:418-422 (1993), in a cynomolgusmonkey renal allograft model according to the method of Cosimi, et al.,J. Immunol., 144:4604-4612 (1990), in a rat nerve allograft modelaccording to the method of Nakao, et al., Muscle Nerve, 18:93-102(1995), in a murine skin allograft model according to the method ofGorczynski and Wojcik, J. Immunol., 152:2011-2019 (1994), in a murinecorneal allograft model according to the method of He, et al.,Opthalmol. Vis. Sci., 35:3218-3225 (1994), or in a xenogeneic pancreaticislet cell transplantation model according to the method of Zeng, etal., Transplantation, 58:681-689 (1994).

The ability of the compounds of the invention to treat graft-versus-hostdisease (GVHD) can be demonstrated in a murine lethal GVHD modelaccording to the method of Harning, et al., Transplantation, 52:842-845(1991).

The ability of the compounds of the invention to treat cancers can bedemonstrated in a human lymphoma metastasis model (in mice) according tothe method of Aoudjit, et al., J. Immunol., 161:2333-2338 (1998).

Combination Treatment

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In one aspect, such therapy includes but is notlimited to the combination of the subject compound with chemotherapeuticagents, therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of thepresent invention may present synergistic or additive efficacy whenadministered in combination with agents that inhibit IgE production oractivity. Such combination can reduce the undesired effect of high levelof IgE associated with the use of one or more PI3Kδ inhibitors, if sucheffect occurs. This may be particularly useful in treatment ofautoimmune and inflammatory disorders (AIID) such as rheumatoidarthritis. Additionally, the administration of PI3Kδ or PI3Kδ/γinhibitors of the present invention in combination with inhibitors ofmTOR may also exhibit synergy through enhanced inhibition of the PI3Kpathway.

In a separate but related aspect, the present invention provides acombination treatment of a disease associated with PI3Kδ comprisingadministering a PI3K δ inhibitor and an agent that inhibits IgEproduction or activity. Other exemplary PI3Kδ inhibitors are applicablefor this combination and they are described, e.g., U.S. Pat. No.6,800,620. Such combination treatment is particularly useful fortreating autoimmune and inflammatory diseases (AIID) including but notlimited to rheumatoid arthritis.

Agents that inhibit IgE production are known in the art and they includebut are not limited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1/mTORC1 inhibitors,mTORC2/TORC2 inhibitors, and any other compounds that inhibitTORC1/mTORC1 and mTORC2/TORC2. Agents that inhibit IgE activity include,for example, anti-IgE antibodies such as for example Omalizumab andTNX-901.

For treatment of autoimmune diseases, the subject compounds orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thesubject compounds or pharmaceutical compositions can be administered incombination with commonly prescribed drugs including but not limited toXolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;

naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another one aspect, this invention also relates to a pharmaceuticalcomposition for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, in combination with an amount of an anti-canceragent (e.g. a chemotherapeutic agent). Many chemotherapeutics arepresently known in the art and can be used in combination with thecompounds of the invention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade(bortezomib), Iressa (gefitinib), Sprycel (Dasatinib), and Adriamycin aswell as a host of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, pκ)tfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide (Casodex), leuprolide, andgoserelin (Zoladex); chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO), 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone,Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Medroxyprogesteroneacetate, matrix metalloproteinase inhibitors, EGFRinhibitors, Pan Her inhibitors, VEGF inhibitors, including as anti-VEGFantibodies such as Avastin, and small molecules such as ZD6474 andSU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055.Anti-Her2 antibodies (such as Herceptin from Genentech) may also beutilized. Suitable EGFR inhibitors include gefitinib, erlotinib, andcetuximab. Pan Her inhibitors include canertinib, EKB-569, andGW-572016. Further suitable anticancer agents include, but are notlimited to, Src inhibitors, MEK-1 kinase inhibitors, MAPK kinaseinhibitors, PI3 kinase inhibitors, and PDGF inhibitors, such asimatinib. Also included are anti-angiogenic and antivascular agentswhich, by interrupting blood flow to solid tumors, render cancer cellsquiescent by depriving them of nutrition. Castration which also rendersandrogen dependent carcinomas non-proliferative, may also be utilized.Also included are IGF1R inhibitors, inhibitors of non-receptor andreceptor tyrosine kinases, and inhibitors of integrin signalling.Additional anticancer agents include microtubule-stabilizing agents7-O-methylthiomethylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176),4-desacetyl-4-methylcarbonatepaclitaxel,3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-desacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel(disclosed in U.S. Ser. No. 09/712,352 filed on Nov. 14, 2000), C-4methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C,epothilone D, desoxyepothilone A, desoxyepothilone B,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo [14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514),[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,-9-dione(as disclosed in U.S. Pat. No. 6,262,094) and derivatives thereof; andmicrotubule-disruptor agents. Also suitable are CDK inhibitors, anantiproliferative cell cycle inhibitor, epidophyllotoxin; anantineoplastic enzyme; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Additional cytotoxic agents include, hexamethyl melamine, idatrexate,L-asparaginase, camptothecin, topotecan, pyridobenzoindole derivatives,interferons, and interleukins. Where desired, the compounds orpharmaceutical composition of the present invention can be used incombination with commonly prescribed anti-cancer drugs such asHerceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®,and Velcade®

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with radiation therapy ininhibiting abnormal cell growth or treating the hyperproliferativedisorder in the mammal. Techniques for administering radiation therapyare known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compoundof the invention in this combination therapy can be determined asdescribed herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source,1-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any 5 solution of radionuclides),e.g., a solution of 1-125 or 1-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the present inventioncan be used in combination with an amount of one or more substancesselected from anti-angiogenesis agents, signal transduction inhibitors,and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-H(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-I. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i. e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The invention also relates to a method of and to a pharmaceuticalcomposition of treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, or an isotopically-labeled derivative thereof, andan amount of one or more therapeutic agents use for the treatment ofcardiovascular diseases.

Examples for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, antiproliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs;

inhibitors of the synthesis and actions of adrenocortical hormones,insulin, oral hypoglycemic agents, and the pharmacology of the endocrinepancreas, agents affecting calcification and bone turnover: calcium,phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such aswater-soluble vitamins, vitamin B complex, ascorbic acid, fat-solublevitamins, vitamins A, K, and E, growth factors, cytokines, chemokines,muscarinic receptor agonists and antagonists; anticholinesterase agents;agents acting at the neuromuscular junction and/or autonomic ganglia;catecholamines, sympathomimetic drugs, and adrenergic receptor agonistsor antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptoragonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-Lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the compounds of theinvention will be co-administered with other agents as described above.When used in combination therapy, the compounds described herein may beadministered with the second agent simultaneously or separately. Thisadministration in combination can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. That is, a compounddescribed herein and any of the agents described above can be formulatedtogether in the same dosage form and administered simultaneously.Alternatively, a compound of the present invention and any of the agentsdescribed above can be simultaneously administered, wherein both theagents are present in separate formulations. In another alternative, acompound of the present invention can be administered just followed byand any of the agents described above, or vice versa. In the separateadministration protocol, a compound of the present invention and any ofthe agents described above may be administered a few minutes apart, or afew hours apart, or a few days apart.

The methods in accordance with the invention may include administering aPI3-kinase δ selective inhibitor with one or more other agents thateither enhance the activity of the inhibitor or compliment its activityor use in treatment. Such additional factors and/or agents may producean augmented or even synergistic effect when administered with aPI3-kinase δ selective inhibitor, or minimize side effects.

In one embodiment, the methods of the invention may includeadministering formulations comprising a PI3-kinase δ selective inhibitorof the invention with a particular cytokine, lymphokine, otherhematopoietic factor, thrombolytic or anti-thrombotic factor, oranti-inflammatory agent before, during, or after administration of thePI3-kinase δ selective inhibitor. One of ordinary skill can easilydetermine if a particular cytokine, lymphokine, hematopoietic factor,thrombolytic of anti-thrombotic factor, and/or anti-inflammatory agentenhances or compliments the activity or use of the PI3-kinase δselective inhibitors in treatment.

More specifically, and without limitation, the methods of the inventionmay comprise administering a PI3-kinase δ selective inhibitor with oneor more of TNF, IL-1, IL-2, IL-3, IL4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN,G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, anderythropoietin. Compositions in accordance with the invention may alsoinclude other known angiopoietins such as Ang-2, Ang4, and Ang-Y, growthfactors such as bone morphogenic protein-1, bone morphogenic protein-2,bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenicprotein-5, bone morphogenic protein-6, bone morphogenic protein-7, bonemorphogenic protein-8, bone morphogenic protein-9, bone morphogenicprotein-10, bone morphogenic protein-11, bone morphogenic protein-12,bone morphogenic protein-13, bone morphogenic protein-14, bonemorphogenic protein-15, bone morphogenic protein receptor IA, bonemorphogenic protein receptor IB, brain derived neurotrophic factor,ciliary neutrophic factor, ciliary neutrophic factor receptor a,cytokine-induced neutrophil chemotactic factor 1, cytokine-inducedneutrophil chemotactic factor 2 alpha, cytokine-induced neutrophilchemotactic factor 2 beta, beta endothelial cell growth factor,endothelin 1, epidermal growth factor, epithelial-derived neutrophilattractant, fibroblast growth factor 4, fibroblast growth factor 5,fibroblast growth factor 6, fibroblast growth factor 7, fibroblastgrowth factor 8, fibroblast growth factor 8b, fibroblast growth factor8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblastgrowth factor acidic, fibroblast growth factor basic, glial cellline-derived neutrophic factor receptor a1, glial cell line-derivedneutrophic factor receptor a2, growth related protein, growth relatedprotein a, growth related protein .beta., growth related protein.gamma., heparin binding epidermal growth factor, hepatocyte growthfactor, hepatocyte growth factor receptor, insulin-like growth factor I,insulin-like growth factor receptor, insulin-like growth factor II,insulin-like growth factor binding protein, keratinocyte growth factor,leukemia inhibitory factor, leukemia inhibitory factor receptor alpha,nerve growth factor, nerve growth factor receptor, neurotrophin-3,neurptrophin-4, placenta growth factor, placenta growth factor 2,platelet derived endothelial cell growth factor, platelet derived growthfactor, platelet derived growth factor A chain, platelet derived growthfactor AA, platelet derived growth factor AB, platelet derived growthfactor B chain, platelet derived growth factor BB, platelet derivedgrowth factor receptor a, platelet derived growth factor receptor beta,pre-B cell growth stimulating factor, stem cell factor, stem cell factorreceptor, transforming growth factor alpha, transforming growth factorbeta, transforming growth factor beta 1, transforming growth factor beta1.2, transforming growth factor beta 2, transforming growth factor beta3, transforming growth factor beta 5, latent transforming growth factorbeta 1, transforming growth factor beta binding protein I, transforminggrowth factor beta binding protein II, transforming growth factor betabinding protein III, tumor necrosis factor receptor type I, tumornecrosis factor receptor type II, urokinase-type plasminogen activatorreceptor, and chimeric proteins and biologically or immunologicallyactive fragments thereof.

The following general methodology described herein provides the mannerand process of making and using the compound of the present inventionand are illustrative rather than limiting. Further modification ofprovided methodology and additionally new methods may also be devised inorder to achieve and serve the purpose of the invention. Accordingly, itshould be understood that there may be other embodiments which fallwithin the spirit and scope of the invention as defined by thespecification hereto.

Representative compounds of the present invention include thosespecified above in Table 1 and pharmaceutically acceptable saltsthereof. The present invention should not be construed to be limited tothem.

General Method of Preparation of Compounds of the Invention

The compounds of the present invention may be prepared by the followingprocesses. Unless otherwise indicated, the variables (e.g., R, R¹, R²,L₁, Cy¹ and Cy²) when used in the below formulae are to be understood topresent those groups described above in relation to formula (I). Thesemethods can similarly be applied to other compounds of formula asprovided herein above with or without modification.

Scheme 1: This scheme provides a synthetic route for the preparation ofa compound of formula (10) wherein all the variables are as describedherein above. The compound of formula (10) can then be converted to thedesired compounds of the invention as provided in schemes 2 and 3 below.

Compound of formula (1) wherein PG is a protecting group such as analkyl group can be reacted with compound of formula (A) wherein R³ andR⁴ can be alkyl or alkoxy groups in the presence of a suitable base suchas n-butyl lithium or lithium diisopropylaminde to give compound offormula (2). Compound of formula (2) can be reacted with a methylGrignard reagent such as methylmagnesium iodide to give compound offormula (3), which can be oxidised by using an oxidising agent such aspyrimidinium dichromate to give compound of formula (4).

Compound of formula (1) can also be reacted with a compound of formula(B) wherein R³ and R⁴ can be alkyl or alkoxy groups in the presence of asuitable base such as n-butyl lithium or lithium diisopropylaminde togive compound of formula (4). Compound of formula (4) can be deprotectedto give compound of formula (5) by using a suitable reagent such asboron tribromide or aluminium chloride. Compound of formula (5) can beacylated with a compound of formula (C) in the presence of a suitablebase such as pyridine to give compound of formula (6). Compound offormula (6) can undergo Baker-venkataraman rearrangement upon treatmentwith a suitable base such as a trialkylamine, a lithium dialkylamide ora lithium disilylamide, e.g. lithium hexamethyl disilazide, to givecompound of formula (7). Compound of formula (7) can be reacted with anacid such as hydrochloric acid to give compound of formula (8). Compoundof formula (8) can be halogenated to give compound of formula (9)wherein X is a halogen by reacting with a halogenating agent such asbromine or N-bromosuccinimide. Compound of formula (9) can be convertedto give compound of formula (10) by reacting with a boronic acid offormula Cy¹-B(OH)₂ wherein Cy¹ is aryl or heteroaryl in the presence ofa palladium catalyst such as tetrakis(triphenylphosphine)palladium(O)and a base such as sodium carbonate.

Scheme 1A: This scheme provides a synthetic route for the preparation ofcompound of formula (10), (12), (14) and (15) wherein all the variablesare as described herein in above, the compound of formula (10), (12),(14) and (15) can then be converted to the desired compounds of theinvention as provided in scheme 2, 3 or 4 below.

This scheme provides a synthetic route for the preparation of compoundof formula (I) wherein all the variables are as described herein inabove

Compound of formula (1a) wherein PG is a protecting group such as alkylgroup can be reacted with hydroxylamine hydrochloride to give compoundof formula (2a). Compound of formula (2a) be reacted withN,N′-carbonyldiimidazole to give compound of formula (3a). Compound offormula (3a) can be reacted with compound of formula (4a) to givecompound of formula (5a). Compound of formula (5a) can be deprotected tocompound of formula (6a) by using a suitable reagent such as borontribromide or aluminium chloride. Compound of formula (6a) can becyclised with benzyllactic acid to compound of formula (12a). Compoundof formula (12a) can be deprotected to compound of formula (12) by usinga suitable reagent such as boron tribromide or aluminium chloride.Compound of formula (12) can be reacted with phosphorus halides to givecompound of formula (10). Compound of formula (10) can be reacted withsodium azide to give compound of formula (14). Compound of formula (14)can be converted to give compound of formula (15) by reacting withtriphenylphosphine.

Illustration of Scheme 1A:

Scheme 2: This scheme provides a synthetic route for the preparation ofcompound of formula (IA-II) from compound of formula (10) wherein allthe variables are as described herein in above Scheme 2

Compound of formula (10) can be reacted with compound of formula (11) inthe presence of a base such as a metal carbonate, e.g., potassiumcarbonate to give compound of formula (IA-I). Alternatively compound offormula (10) can be converted into compound of formula (12) by reactingwith a suitable reagent such as dimethyl sulfoxide. Compound of formula(12) can be subjected to Mitsunobu reaction with compound of formula(11) in the presence of a dialkyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine to afford compound of formula(IA-I).

Scheme 3: This scheme provides a synthetic route for the preparation ofcompound of formula (IA-II) from compound of formula (10) wherein allthe variables are as described herein in above

Compound of formula (10) can be reacted with compound of formula (11a)in the presence of a base such as a metal carbonate, e.g., potassiumcarbonate to give compound of formula (IA-II). Alternatively compound offormula (10) can be converted into compound of formula (12) by reactingwith a suitable reagent such as dimethyl sulfoxide. Compound of formula(12) can be subjected to Mitsunobu reaction with compound of formula(11a) in the presence of a dialkyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine to afford compound of formula(IA-II).

Scheme 4: This scheme provides a synthetic route for the preparation ofcompound of formula (IA-IV) from compound of formula (10) wherein allthe variables are as described herein in above

Compound of formula (10) can be reacted with a metal azide such assodium azide to give compound of formula (14) which can be reduced tocompound of formula (15) by using methods known to those skilled in theart. Compound of formula (15) can be reacted with compound of formula(11b) or (11c) in the presence of a suitable base such asN-ethyldiisopropylamine to give respectively the compound of formula(IA-IV) and (IA-III).

Similar methodologies with certain modifications as known to thoseskilled in the art can be used to synthesize compound of formula of (I)and (IA) wherein all the variable are to be understood to present thosegroups described above in relation to formula (I) and (IA) usingsuitable intermediates and reagents.

EXPERIMENTAL

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

List of Intermediates

Intermediate 1: 2-fluoro-6-methoxybenzaldehyde: n-BuLi (1.6M in hexane,74.3 ml, 0.118 mol) was added dropwise to a solution of diisopropylamine(13.23 g, 0.130 mol) in THF (50 ml) at 0° C., maintained for 15 min. andcooled to −78° C. 3-Fluoroanisole (15 g, 0.118 mol) in THF (5° ml) wasadded, stirred at −78° C. for 1 h, and N,N-dimethylformamide (6.75 ml)was added and stirred for further 1 h. The reaction mixture was quenchedwith 2N HCl solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated to afford the titlecompound as a red waxy solid (17.45 g, 95%) which was used withoutpurification in the next step.

Intermediate 2: 1-(2-fluoro-6-methoxyphenyl)ethanol: To an ice-coldsolution of methylmagnesium iodide prepared from magnesium (8.8 g, 0.366mol) and methyliodide (52.06 g, 0.366 mol) in diethyl ether (150 ml),intermediate 1 (18.85 g, 0.122 mol) in diethyl ether (50 ml) was addedand warmed to room temperature. After 12 h, the reaction mixture wascooled to 0° C., quenched with dilute aqueous HCl and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound as ared liquid (18.9 g, 99%) which was used without purification in the nextstep.

Intermediate 3: 1-(2-fluoro-6-methoxyphenyl)ethanone: Pyridiniumdichromate (44 g, 0.116 mol) was added to a solution of intermediate 2(13.1 g, 0.077 mol) in DMF (130 ml) and stirred at room temperature for12 h. Water (300 ml) was added to the reaction mixture and diluted withethyl acetate and filtered through celite. The organic layer was washedwith brine solution and dried over sodium sulphate and concentratedunder reduced pressure to afford the title compound as a brown colourliquid (9.2 g, 70%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.73 (dd, J=15.1,8.4 Hz, 1H), 6.73 (m, 2H), 3.85 (s, 3H), 2.53 (s, 3H).

Intermediate 4: 1-(2-fluoro-6-hydroxyphenyl)ethanone: To an ice-coldsolution of intermediate 3 (9.0 g, 53.5 mmol) in dichloromethane (70ml), aluminium chloride (14.3 g, 0.107 mol) was added and warmed to roomtemperature. After 12 h, the reaction mixture was quenched with aqueous2N HCl and extracted with ethyl acetate. The organic layer was washedwith water, dried over sodium sulphate and concentrated under reducedpressure to afford the title compound as a brown liquid (5.48 g, 66%).¹H-NMR (δ ppm, CDCl₃, 400 MHz): 12.72 (s, 1H), 7.40 (m, 1H), 6.78 (d,J=8.5 Hz, 1H), 6.62 (dd, J=11.3, 8.3 Hz, 1H), 2.69 (d, J=7.2 Hz, 3H).

Intermediate 5: 2-acetyl-3-fluorophenyl acetate: Pyridine (7.8 ml) andacetyl chloride (3.60 g, 45.93 mmol) were added to an ice-cold solutionof intermediate 4 (5.9 g, 38.27 mmol) in dichloromethane (50 ml) andheated to 45° C. After 3 h, water was added to the mixture and extractedinto ethyl acetate. The organic layer was washed with water, dried oversodium sulphate and the solvents evaporated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a yellow liquid (6.2 g, 82%). ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.45 (m, 1H), 7-05 (t, J=8.9 Hz, 1H), 6.93 (d,J=8.1 Hz, 1H), 2.56 (d, J=3.3 Hz, 3H), 2.27 (s, 3H).

Intermediate 6: 5-hydroxy-2-methyl-4H-chromen-4-one: To an ice-coldsolution of intermediate 5 (3.0 g, 15.29 mmol) in dimethylsulphoxide (15ml), sodium hydride (0.367 mg, 15.29 mmol) was added and heated to 100°C. After 12 h, the reaction mixture was quenched with aqueous 10% HCland extracted with ethyl acetate. The organic layer was washed withwater, dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withethyl acetate:petroleum ether to afford the title compound as a yellowliquid (1.3 g, 48%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 12.54 (s, 1H), 7.50(t, J=8.3 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.10(s, 1H), 2.38 (s, 3H).

Intermediate 7: 5-methoxy-2-methyl-4H-chromen-4-one: To a solution ofintermediate 6 (1.12 g, 15.29 mmol) in DMF (10 ml), potassium carbonate(1.31 g, 9.53 mmol) and methyl iodide were added and heated to 50-60° C.After 12 h, water was added to the mixture and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulphate and concentrated to afford the title compound as a yellow solid(0.85 g, 70%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.52 (t, J=8.4 Hz, 1H),6.97 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.07 (s, 1H), 3.96 (s,3H), 2.29 (s, 3H).

Intermediate 8: 3-bromo-5-methoxy-2-methyl-4H-chromen-4-one:N—Bromosuccinimide (0.795 g, 4.46 mmol) was added to a solution ofintermediate 7 (0.85 g, 4.46 mmol) in DMF (10 ml), at RT. After 12 h,water was added to the mixture and extracted with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound as ayellow solid (0.985 g, 82%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.56 (t,J=8.0 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 3.96 (s,3H), 2.58 (s, 3H).

Intermediate 9: 3-(3-fluorophenyl)-5-methoxy-2-methyl-4H-chromen-4-one:To a solution of Intermediate 8 (0.985 g, 3.66 mmol) and3-Fluorophenylboronic acid (0.819 g, 5.85 mmol) in dioxan (10 ml),potassium carbonate (1.51 g, 10.98 mmol) and water (2 ml) were added anddegassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.253 g,0.219 mmol) was added under nitrogen at RT and the reaction mixturerefluxed for 12 h. The solvent was evaporated completely and water wasadded to the residue and extracted with ethyl acetate, organic layerdried over sodium sulphate and concentrated. The residue obtained waspurified by column chromatography w to afford the title compound as ayellow solid (0.875 g, 81%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.55 (t,J=8.4 Hz, 1H), 7.38 (dd, J=13.9, 7.8 Hz, 1H), 7.06-6.99 (m, 4H), 6.79(d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.25 (s, 3H).

Intermediate 10:2-(bromomethyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one: To asolution of Intermediate 9 (0.875 g, 3.07 mmol in carbon tetrachloride(10 ml) N-bromosuccinimide (0.547 g, 3.07 mmol) was added and heated to80° C., azobisisobutyronitrile (20 mg) added and stirred at the sametemperature for 12 h. The reaction mixture was cooled to RT, dilutedwith dichloromethane and washed with water. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as an off-whitesolid (0.440 g, 39% yield) which was used without purification in thenext step.

Intermediate 11: 4-bromo-2-fluoro-1-isopropoxybenzene: To a solution of4-bromo-2-fluorophenol (10 g, 52.35 mmol) in THF (100 ml), isopropylalcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6 g, 78.52 mmol)were added and heated to 45° C. followed by diisopropylazodicarboxylate(15.4 ml, 78.52 mmol). The mixture was refluxed for 1 h, concentratedand the residue was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as a colourlessliquid (13.1 g, 99%) which was used without purification in the nextstep.

Intermediate 12:2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:Potassium acetate (10.52 g, 107.2 mmol) and bis(pinacolato)diboron (15g, 58.96 mmol) were added to a solution of intermediate 11 (10.52 g,107.2 mmol) in dioxane (125 ml), and the solution was degassed for 30min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(4.4 g, 5.36 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12 h, the reaction mixture was filtered through celite andconcentrated. The crude product was purified by column chromatographywith ethyl acetate:petroleum ether to afford the title compound as ayellow oil (13.9 g, 99%) which was used without purification in the nextstep.

Intermediate 13:3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; Toa solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (11.0 g, 42.14mmol) in DMF 110 ml), ethanol (55 ml) and water (55 ml), intermediate 12(23.4 g, 84.28 mmol) and sodium carbonate (13.3 g, 126.42 mmol) wereadded and degassed for 30 min. Tetrakis(triphenylphosphine)palladium(0)(2.4 g, 2.10 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12 h, the reaction mixture was filtered though celite,concentrated and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure. Thecrude product was triturated with diethyl ether, filtered and driedunder vacuum to afford the title compound as light brown solid (3.2 g,26% yield) which is used as such for the next step.

Intermediate 14: 5-fluoro-2-methyl-4H-chromen-4-one: To a solution ofIntermediate 5 (5.0 g, 25.48 mmol) in THF (70 ml) cooled to −78° C.,lithium bis(trimethylsilylamide) (1M in THF, 25.45 ml, 25.48 mmol) wasadded maintained at the same temperature for 2 h. The mixture was warmedto RT and stirred for 4 h. The reaction was quenched by the additionaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulphate and thesolvents removed. The crude product was dissolved in dioxane (8 ml) andsulphuric acid (8 ml) was added and heated to reflux for 4 h. Aqueoussodium bicarbonate solution was added to the mixture and extracted withethyl acetate. The organic layer was washed with water, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as an off-whitesolid (0.91 g, 20%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.58 (m, 1H), 7.22(d, J=8.5 Hz, 1H), 7.03 (t, J=9.7 Hz, 1H), 6.11 (s, 1H), 2.34 (s, 3H).

Intermediate 15: 3-bromo-5-fluoro-2-methyl-4H-chromen-4-one: To asolution of intermediate 14 (0.910 g, 5.10 mmol) in DMF (8 ml),N-bromosuccinimide (0.908 g, 5.10 mmol) was added at RT. After 12 h, thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulphate and the solvent removed to afford the title compound as anoff-white solid (0.410 g, 31%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.62 (m,1H), 7.25 (d, J=8.28 Hz, 1H), 7.09 (t, J=9.6 Hz, 1H), 2.63 (s, 3H).

Intermediate 16: 5-fluoro-3-(3-fluorophenyl)-2-methyl-4H-chromen-4-one:To a solution of intermediate 15 (0.150 g, 0.583 mmol) and3-fluorophenylboronic acid (0.129 g, 0.933 mmol) in dioxan (2 ml),potassium carbonate (0.241 g, 1.75 mmol) and water (0.5 ml) were addedand degassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.040g, 0.035 mmol) was added under nitrogen at RT and the reaction mixturewas refluxed for 12 h. The solvent was evaporated completely and waterwas added to the residue and extracted with ethyl acetate, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as a yellow solid(0.100 g, 63%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.61 (m, 1H), 7.42 (dd,J=14.2, 8.0 Hz, 1H), 7.09-6.99 (m, 4H), 2.29 (s, 3H).

Intermediate 17:2-(bromomethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To asolution of Intermediate 16 (0.245 g, 0.900 mmol in carbon tetrachloride(5 ml)N-bromosuccinimide (0.160 g, 0.900 mmol) was added and heated to80° C., azobisisobutyronitrile (10 mg) added and stirred at the sametemperature for 12 h. The reaction mixture was cooled to RT, dilutedwith dichloromethane and washed with water. The organic layer was driedover sodium sulphate and concentrated under reduced pressure to affordthe title compound as red semi solid (0.326 g) which was used withoutpurification in the next step.

Intermediate 18: 2-acetyl-3-fluorophenyl propionate: Pyridine (7.2 ml)and propionyl chloride (3.85 g, 41.65 mmol) were added to an ice-coldsolution of intermediate 4 (5.35 g, 37.70 mmol) in dichloromethane (40ml) and heated to 45° C. After 3 h, water was added to the mixture andextracted into ethyl acetate. The organic layer was washed with water,dried over sodium sulphate and the solvents evaporated. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as a yellow liquid(6.4 g, 81%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.44 (dt, J=8.2, 6.4, 1H),7-05 (t, J=8.9 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H),2.55 (s, 3H), 1.25 (t, J=7.5 Hz, 3H).

Intermediate 19: 2-ethyl-5-fluoro-4H-chromen-4-one: To a solution ofIntermediate 18 (5.1 g, 24.28 mmol) in DMSO (20 ml) cooled to 0° C.,sodium hydride (0.582 g, 24.28 mmol) was added maintained at the sametemperature for 1 h. The mixture was warmed to RT and stirred for 12 h.The reaction was quenched by the addition of 2N HCl and extracted withethyl acetate. The organic layer was washed with water, dried oversodium sulphate and the solvents removed. The crude product wasdissolved in dioxane (20 ml) and sulphuric acid (6 ml) was added andheated to reflux for 12 h. Aqueous sodium bicarbonate solution was addedto the mixture and extracted with ethyl acetate. The organic layer waswashed with water, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as yellow liquid (2.49 g, 51%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz):7.58 (dt, J=13.9, 5.6 Hz, 1H), 7.54 (d, J=5.6 Hz, 1H), 7.04 (t, J=8.4Hz, 1H), 6.14 (s, 1H), 2.66 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).

Intermediate 20: 3-bromo-2-ethyl-5-fluoro-4H-chromen-4-one: To asolution of intermediate 19 (2.49 g, 12.95 mmol) in DMF (15 ml),N-bromosuccinimide (2.30 g, 12.95 mmol) was added at RT. After 12 h, thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulphate and the solvent removed to afford the title compound as anreddish brown solid (2.60 g, 74%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.62(dt, J=13.8, 5.5 Hz, 1H), 7.25 (d, J=5.6 Hz, 1H), 7.09 (dt, J=9.5, 1.1Hz, 1H), 2.99 (q, J=7.6 Hz, 2H), 1.37 (t, J=7.6 Hz, 3H).

Intermediate 21: 2-ethyl-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 20 (2.60 g, 9.59 mmol) and3-fluorophenylboronic acid (2.13 g, 15.34 mmol) in dioxan (15 ml),potassium carbonate (3.97 g, 28.77 mmol) and water (2 ml) were added anddegassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.664 g,0.575 mmol) was added under nitrogen at RT and the reaction mixture wasrefluxed for 12 h. The solvent was evaporated completely and water wasadded to the residue and extracted with ethyl acetate, dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (1.20 g, 44%). ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.61 (dt, J=13.8, 5.5 Hz, 1H), 7.41 (dd, J=14.0,7.8 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.10-6.98 (m, 4H), 2.59 (q, J=7.6Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).

Intermediate 22:2-(1-bromoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To asolution of Intermediate 21 (0.500 g, 1.86 mmol in carbon tetrachloride(5 ml) N-bromosuccinimide (0.331 g, 0.900 mmol) was added and heated to80° C., azobisisobutyronitrile (5 mg) added and stirred at the sametemperature for 12 h. The reaction mixture was cooled to RT, dilutedwith dichloromethane and washed with water. The organic layer was driedover sodium sulphate and concentrated under reduced pressure to affordthe title compound as a off-white solid (0.460 g, 68%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 7.68 (dt, J=8.4, 5.4 Hz, 1H), 7.46 (dd, J=14.1, 8.0 Hz,1H), 7.37 (d, J=8.5 Hz, 1H), 7.15-7.05 (m, 4H), 4.91 (q, J=6.9 Hz, 1H),1.98 (d, J=6.9 Hz, 3H).

Intermediate 23:5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: To asolution of Intermediate 22 (0.950 g, 2.60 mmol) in DMSO (9.5 ml),n-butanol (0.47 ml) was added and heated to 120° C. for 3 h., Thereaction mixture was cooled to RT, quenched with water and extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as a yellow solid (0.700 g, 89%). ¹H-NMR (δ ppm, DMSO-D₆,400 MHz): 7.84 (dt, J=14.2, 5.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.49(m, 1H), 7.27 (m, 2H), 7.15 (m, 2H), 5.62 (d, J=4.8 Hz, 1H), 4.44 (m,1H), 1.37 (d, J=6.5 Hz, 3H).

Intermediate 23a and 23b:(+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one and(−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: Thetwo enantiomerically pure isomers were separated by preparative SFCconditions from intermediate 23 (0.300 g) on a CHIRALPAK AD-H column(250×4.6 mm; 5 μm) using methanol: CO₂ (20:80) as the mobile phase at aflow rate of 3.0 ml/min.

Intermediate 23a: Off-white solid (0.140 g). e.e. 100%. Rt: 2.41 min.[α]²⁵ _(D) 4.17 (c=1, MeOH). Mass: 302.9 (M⁺).

Intermediate 23b: Off-white solid (0.143 g). e.e. 100%. Rt: 3.06 min.[α]²⁵ _(D) −4.17 (c=1, MeOH). Mass: 302.9 (M+).

Intermediate 24: 2-acetyl-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

DMSO (0.657 ml, 9.26 mmol) was added to dichloromethane (8 ml) cooled to−78° C., followed by oxalyl chloride (0.40 ml, 4.63 mmol). After 10 min.intermediate 23 (0.700 g, 2.31 mmol) in dichloromethane (4 ml) was addeddropwise and stirred for 20 min. Triethylamine (1.3 ml) was added andstirred for 1 h. The reaction mixture was quenched with water andextracted with dichloromethane. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a yellow solid (0.450 g, 65%). ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.71 (dt, J=11.2, 2.9 Hz, 1H), 7.40 (m, 2H),7.14-7.00 (m, 4H), 2.32 (s, 3H).

Intermediate 25:(R)/(S)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one:To intermediate 24 (0.280 g, 0.93 mmol), S-Alpine borane (0.5M in THF,10 ml) was added and heated to 70° C. for 24 h. The reaction mixture wasquenched with aq. 2N HCl, and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withethyl acetate:petroleum ether to afford the title compound as anoff-white solid (0.200 g, 71%). Enantiomeric excess: 73%, enriched inthe late eluting isomer (retention time: 8.72 min. as determined by HPLCon a chiralpak AD-H column.

Intermediate 26:(R)/(S)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one:To intermediate 24 (0.280 g, 0.93 mmol), R-Alpine borane (0.5M in THF,2.8 ml) was added and heated to 60° C. for 24 h. The reaction mixturequenched with aq. 2N HCl, and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withethyl acetate:petroleum ether to afford the title compound as a paleyellow solid (0.110 g, 37%). Enantiomeric excess: 94.6%, enriched in thefast eluting isomer (retention time: 7.16) as determined by HPLC on achiralpak AD-H column.

Intermediate 27:2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.800 g,2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) wasadded and stirred at RT for 30 min. To this mixture intermediate 22(0.500 g, 1.44 mmol) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as a off-white solid (0.300 g, 38%). ¹H-NMR (δ ppm, DMSO-d₆₃,400 MHz): 8.02 (s, 1H), 7.94 (s, 1H), 7.84 (dt, J=8.4, 5.7 Hz, 1H), 7.47(d, J=8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, J=8.8, 2.3 Hz, 1H), 6.87 (s,2H), 5.88 (q, J=7.0 Hz, 1H), 1.82 (d, J=7.0 Hz, 3H).

Intermediate 28: 3-bromo-2-(1-bromoethyl)-5-fluoro-4H-chromen-4-one: Thetitle compound was obtained as a brown solid (3.60 g, 94%) by using aprocedure that is similar to the one described for intermediate 22 fromintermediate 20 (3.0 g, 11.06 mmol), carbon tetrachloride (30 ml)N-bromosuccinimide (1.96 g, 11.06 mmol) and azobisisobutyronitrile (30mg) which is used as such in a next step.

Intermediate 29:2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-bromo-5-fluoro-4H-chromen-4-one:The title compound was obtained as a brown solid (0.800 g, 36%) by usinga procedure that is similar to the one described for intermediate 27from intermediate 13 (1.11 g, 4.28 mmol), cesium carbonate (1.39 g, 4.28mmol), DMF (5 ml) and intermediate 28. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.37 (s, 1H), 7.62 (dt, J=8.4, 5.4 Hz, 1H), 7.45 (dd, J=11.5, 2.1 Hz,1H), 7.39 (m, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.14-7.04 (m, 2H), 6.60 (q,J=7.1 Hz, 1H), 5.67 (s, 2H), 4.65 (q, J=6.0 Hz, 1H), 2.08 (d, J=7.1 Hz,3H), 1.41 (d, J=6.1 Hz, 6H).

Intermediate 30: 2-ethyl-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.680 g, 54%) byusing a procedure that is similar to the one described for intermediate21 from intermediate 20 (1.20 g, 4.42 mmol), 4-fluorophenylboronic acid(0.991 g, 7.08 mmol), dioxan (9 ml), potassium carbonate (1.83 g, 13.27mmol), water (1.2 ml) and tetrakis(triphenylphosphine)palladium(0)(0.306 g, 0.265 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.60 (dt, J=8.3,5.5 Hz, 1H), 7.27 (m, 3H), 7.13 (t, J=8.7 Hz, 2H), 7.04 (t, J=9.1 Hz,1H), 2.55 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H).

Intermediate 31:2-(1-bromoethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one: The titlecompound was obtained as a brown solid (0.740 g, 85%) by using aprocedure that is similar to the one described for intermediate 22 fromintermediate 30 (0.680 g, 2.37 mmol), carbon tetrachloride (10 ml)N-bromosuccinimide (0.423 g, 2.37 mmol) and azobisisobutyronitrile (30mg). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.67 (dt, J=8.4, 5.5 Hz, 1H), 7.37(m, 3H), 7.18 (t, J=8.7 Hz, 2H), 7.09 (t, J=8.5 Hz, 1H), 4.92 (q, J=6.9Hz, 1H), 1.97 (d, J=6.9 Hz, 3H).

Intermediate 32: 2-ethyl-5-fluoro-3-phenyl-4H-chromen-4-one: The titlecompound was obtained as a off-white solid (0.600 g, 50%) by using aprocedure that is similar to the one described for intermediate 21 fromintermediate 20 (1.20 g, 4.42 mmol), phenylboronic acid (0.864 g, 7.08mmol), dioxan (9 ml), potassium carbonate (1.83 g, 13.27 mmol), water(1.2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.306 g, 0.265mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.61 (dt, J=8.4, 5.5 Hz, 1H),7.45 (m, 3H), 7.28 (m, 3H), 7.05 (dt, J=8.5, 1.3 Hz, 1H), 2.60 (q, J=7.6Hz, 2H), 1.28 (t, J=7.5 Hz, 3H).

Intermediate 33: 2-(1-bromoethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as a brown solid (0.590 g, 76%) by usinga procedure that is similar to the one described for intermediate 22from intermediate 32 (0.600 g, 2.23 mmol), carbon tetrachloride (9 ml)N-bromosuccinimide (0.398 g, 2.37 mmol) and azobisisobutyronitrile (30mg). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.66 (dt, J=8.4, 5.5 Hz, 1H), 7.48(m, 3H), 7.37 (m, 3H), 7.08 (t, J=9.8 Hz, 1H), 4.95 (q, J=6.8 Hz, 1H),1.97 (d, J=6.9 Hz, 3H).

Intermediate 34:2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.800 g,2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) wasadded and stirred at RT for 30 min. To this mixture intermediate 22(0.500 g, 1.44 mmol) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as a off-white solid (0.300 g, 38%). ¹H-NMR (δ ppm, DMSO-d₆₃,400 MHz): 8.02 (s, 1H), 7.94 (s, 1H), 7.84 (dt, J=8.4, 5.7 Hz, 1H), 7.47(d, J=8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, J=8.8, 2.3 Hz, 1H), 6.87 (s,2H), 5.88 (q, J=7.0 Hz, 1H), 1.82 (d, J=7.0 Hz, 3H).

Intermediate 35:2-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)isoindoline-1,3-dione:To a solution of phthalimide (0.420 g, 2.88 mmol) in DMF (4 ml),potassium carbonate (0.43 g, 2.88 mmol) was added and stirred at RT for30 min. To this mixture intermediate 22 (0.400 g, 2.88 mmol) was addedand stirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with ethyl acetatel:pet. ether toafford the title compound as a off-white solid (0.350 g, 32%). ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.77 (m, 4H), 7.63 (dt, J=8.4, 5.4 Hz, 1H), 7.34(d, J=8.5 Hz, 1H), 7.28 (m, 1H), 7.08 (m, 1H), 6.97 (m, 2H), 6.86 (d,J=7.4 Hz, 1H), 5.79 (q, J=7.2 Hz, 1H), 1.81 (d, J=7.2 Hz, 3H).

Intermediate 36:2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To asolution of intermediate 35 (0.350 g, 0.847 mmol) in methanol (3.5 ml),hydrazine hydrate (0.070 g, 1.27 mmol) was added and refluxed for 3 h.The reaction mass cooled, filtered and washed with chloroform. Thefilterate was concentrated to afford the title compound as a brown solid(0.200 g, 78%). ¹H-NMR (δ ppm, DMSO-d₆₃, 400 MHz): 7.29 (dt, J=8.0, 6.4Hz, 1H), 7.19 (q, J=8.2 Hz, 1H), 7.02 (m, 3H), 6.69 (d, J=8.2 Hz, 1H),6.59 (t, J=8.8 Hz, 1H), 4.12 (q, J=6.6 Hz, 1H), 1.32 (d, J=6.7 Hz, 3H).

Intermediate 37: 4-bromo-1-(difluoromethoxy)-2-fluorobenzene: To asolution of 4-bromo-2-fluorophenol (1.00 g, 5.23 mmol) in DMF (17 ml)and water (2.3 ml), sodiumchlorodifluoroacetate (1.60 g, 1047 mmol) andpotassium carbonate (0.866 g, 6.282 mmol) were added. The flask waspurged with nitrogen for 15 min. and heated to 100° C. After 2.5 h,cooled to room temperature, con.HCl (2.5 ml) and water (2.5 ml) wereadded and stirred for 1 h. The reaction mixture was cooled to 0° C.,quenched with aq. 1N sodium hydroxide solution, extracted with ethylacetate and dried over sodium sulphate and concentrated. The crudeproduct was purified by column chromatography with ethyl acetatel:pet.ether to afford the title compound as a colourless liquid (0.545 g,43%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.36 (dd, J=9.7, 2.3 Hz, 1H), 7.28(td, J=8.7, 1.5 Hz, 1H), 7.15 (t, J=8.3 Hz, 1H), 6.71 (t, J=73.0 Hz,1H).

Intermediate 38:2-(4-(difluoromethoxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:The title compound was obtained as a yellow liquid (0.475 g, 76%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 35 (0.520 g, 2.15 mmol), potassium acetate (0.423g, 4.31 mmol), bis(pinacolato)diboron (0.602 g, 2.37 mmol) dioxane (10ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.088 g, 0.107 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.59 (m, 2H), 7.23 (t, J=7.9 Hz, 1H), 6.75 (t, J=73.5 Hz, 1H),1.35 (s, 12H).

Intermediate 39:3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a light brown solid (0.321 g, 28%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 38 (1.70 g, 5.74 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 3.83 mmol), DMF (5ml), ethanol (2.5 ml), water (2.5 ml) sodium carbonate (1.21 g, 11.49mmol) and tetrakis(triphenylphosphine)palladium(0) (0.221 g, 0.191 mmol)¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.66 (s, 1H), 8.21 (s, 1H), 7.62 dd,J=10.6, 5.4 Hz, 1H), 7.51 (m, 2H), 7.48 (t, J=73.2 Hz, 1H), 6.92 (s,2H).

Intermediate 40: 4-(4-bromo-2-fluorophenoxy)tetrahydro-2H-pyran: To asolution of 4-bromo-2-fluorophenol (3.89 g, 20.39 mmol) in THF (50 ml),4-hydroxytetrahydropyran (2.50 g, 24.47 mmol) and triphenylphosphine(8.02 g, 30.58 mmol) were added and heated to reflux for 2 h. Thereaction mixture was cooled to 0° C., diisopropylazodicarboxylate (6.02ml, 30.58 mmol) was added and hated to reflux for 12 h. The reactionmixture was concentrated and the crude product was purified by columnchromatography with ethyl acetatel:pet. ether to afford the titlecompound as a colourless liquid (0.3.6 g, 83%). ¹H-NMR (δ ppm, CDCl₃,400 MHz): 7.26 (dd, J=10.4, 2.1 Hz, 1H), 7.18 (m, 1H), 6.90 (t, J=8.7Hz, 1H), 4.45 (m, 1H), 4.01 (m, 2H), 3.57 (m, 2H), 2.02-1.76 (m, 4H).

Intermediate 41:2-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:The title compound was obtained as a off-white solid (2.50 g, 59%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 40 (3.50 g, 16.49 mmol), potassium acetate (3.25 g,32.99 mmol), bis(pinacolato)diboron (4.60 g, 18.14 mmol) dioxane (40 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(1.34 g, 1.64 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.50 (m, 2H), 6.97(t, J=7.9 Hz, 1H), 4.54 (m, 1H), 4.00 (m, 2H), 3.57 (m, 2H), 2.02-1.76(m, 4H), 1.31 (s, 12H).

Intermediate 42: 1-(4-bromo-2-fluorophenyl)-2-methylpropan-1-ol: To anice-cold solution of isopropylmagnesium bromide prepared from magnesium(8.8 g, 0.147 mol) and 2-bromopropane (18.1 g, 0.147 mol) in diethylether (80 ml), 4-bromo-2-fluorobenzaldehyde (10.0 g, 0.049 mol) indiethyl ether (20 ml) was added and warmed to room temperature. After 12h, the reaction mixture was cooled to 0° C., quenched with diluteaqueous HCl and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure toafford the title compound as a brown liquid (12.0 g, 99%) which was usedwithout purification in the next step.

Intermediate 43: 1-(4-bromo-2-fluorophenyl)-2-methylpropan-1-one: Thetitle compound was obtained as a light brown liquid (0.5.8 g, 59%) byusing a procedure that is similar to the one described for intermediate3 from intermediate 42 (10.0 g, 40.46 mmol), pyridinium dichromate (22.8g, 60.70 mmol) and DMF (50 ml) which was used without purification inthe next step.

Intermediate 44: 6-bromo-3-isopropyl-1H-indazole: To a solution ofintermediate 42 (5.80 g, 23.66 mmol) in ethylene glycol (39 ml),hydrazine hydrate (2.3 g, 47.32 mmol) was added and heated to 160° C.for 12 h. The reaction mixture was cooled and quenched with ethylacetate and extracted with ethyl acetate, dried over sodium sulphate andconcentrated to afford the title compound as pale yellow solid (3.0 g,54%). ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 9.80 (s, 1H), 7.63 (d, J=8.7 Hz,1H), 7.61 (s, 1H), 7.24 (dd, J=8.5, 1.5 Hz, 1H), 3.43 (quintet, J=7.0Hz, 1H), 1.45 (d, J=6.9 Hz, 6H).

Intermediate 45: tert-butyl6-bromo-3-isopropyl-1H-indazole-1-carboxylate: To a solution ofintermediate 44 (2.0 g, 8.36 mmol) in acetonitrile (20 ml),4-dimethylaminopyridine (0.102 g, 0.836 mmol), Boc-anhydride (1.82 g,8.36 mmol) were added at 20-25° C. followed by triethylamine (0.846 g,8.36 mmol). After 12 h, the reaction mixture was concentrated andquenched with water, extracted with ethyl acetate, dried with ethylacetate and concentrated. The crude product was purified by columnchromatography with ethyl acetatel:pet. ether to afford the titlecompound as a colourless liquid (1.70 g, 61%). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 8.29 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.40 (dd, J=8.5, 1.5 Hz,1H), 3.41 (quintet, J=7.0 Hz, 1H), 1.71 (s, 9H), 1.46 (d, J=7.0 Hz, 6H).

Intermediate 46: tert-butyl3-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylateThe title compound was obtained as a off-white solid (1.50 g, 79%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 45 (1.70 g, 5.01 mmol), potassium acetate (0.980 g,10.02 mmol), bis(pinacolato)diboron (1.40 g, 5.51 mmol) dioxane (17 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.200 g, 0.250 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.59 (s, 1H),7.74 (d, J=7.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 3.45 (quintet, J=7.0 Hz,1H), 1.73 (s, 9H), 1.48 (d, J=7.0 Hz, 6H), 1.36 (s, 12H).

Intermediate 47: tert-butyl4-(4-bromo-2-fluorophenoxy)piperidine-1-carboxylate: To a solution of4-bromo-2-fluorophenol (1.66 g, 8.69 mmol) in THF (20 ml),4-hydroxy-1-Bocpiperidine (2.10 g, 10.43 mmol) and triphenylphosphine(3.42 g, 13.04 mmol) were added and heated to 45° C. After 30 min.diisopropylazodicarboxylate (2.56 ml, 13.04 mmol) was added and stirredfor 12 h. The reaction mixture was concentrated and the crude productwas purified by column chromatography with ethyl acetatel:pet. ether toafford the title compound as a colourless liquid (1.20 g, 38%). ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 7.25 (dd, J=8.7, 2.7 Hz, 1H), 7.18 (m, 1H),6.89 (t, J=8.7 Hz, 1H), 4.42 (septet, J=3.6 Hz, 1H), 3.73 (m, 2H), 3.34(m, 2H), 1.92-1.72 (m, 4H), 1.46 (s, 9H).

Intermediate 48: tert-butyl4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate:The title compound was obtained as a pale yellow solid (1.90 g, 99%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 47 (1.10 g, 2.92 mmol), potassium acetate (0.573 g,5.84 mmol), bis(pinacolato)diboron (0.816 g, 3.21 mmol) dioxane (12 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.230 g, 0.292 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.51 (m, 2H),6.98 (t, J=7.9 Hz, 1H), 4.53 (septet, J=3.5 Hz, 1H), 3.72 (m, 2H), 3.36(m, 2H), 1.92-1.74 (m, 4H), 1.45 (s, 9H), 1.31 (s, 12H).

Intermediate 49: 2-(2-fluoro-4-nitrophenylamino) ethanol: To a solutionof 3,4-difluoro-1-nitrobenzene (3.50 g, 22.0 mmol) in acetonitrile (35ml), ethanolamine (1.98 ml, 33.0 mmol) was added and heated at refluxfor 4 h. The reaction mass was concentrated and residue was trituratedwith pet. ether and filtered and dried under vacuum to afford the titlecompound as a yellow solid (3.2 g, 73%) which was used withoutpurification in the next step.

Intermediate 50: 2-(4-amino-2-fluorophenylamino)ethanol: To a solutionof intermediate 49 (3.2 g, 15.98 mmol) in methanol, palladium oncharcoal (0.800 g, 5% Pd/C) was added and hydrogenated in an autoclaveat 4 kg/cm² for 4 h at room temperature. The reaction mass was filteredthrough celite, washed with methanol and concentrated under vacuum toafford the title compound as brown liquid (3.00 g, 99%) which was usedwithout purification in the next step.

Intermediate 51: 2-(4-bromo-2-fluorophenylamino)ethanol: To intermediate50 (3.00 g, 17.62 mmol), 48% hydrobromic acid (36 ml) was added andcooled to 0° C., sodium nitrite (3.64 g, 52.88 mmol) in water (42 ml)was added dropwise and stirred at room temperature for 15 min. Thereaction mixture was cooled again to 0° C. and copper(I)bromide (3.79 g,26.44 mmol) was added and heated to 140° C. for 4 h. The reaction masswas cooled to room temperature and basified with saturated sodiumbicarbonate solution, filtered through celite, washed with ethylacetate. The aqueous layer was extracted with ethyl acetate, dried withsodium sulphate and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate:pet. ether to afford the titlecompound as a brown liquid (1.40 g, 34%). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.14 (m, 2H), 6.61 (t, J=8.7 Hz, 1H), 4.21 (br s, 1H), 3.86 (t,J=5.1 Hz, 2H), 3.32 (t, J=5.0 Hz, 2H), 1.72 (s, 1H).

Intermediate 52:2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)ethanol:The title compound was obtained as a brown liquid (1.40 g, 58%) by usinga procedure that is similar to the one described for intermediate 12from intermediate 50 (1.40 g, 2.92 mmol), potassium acetate (1.17 g,11.95 mmol), bis(pinacolato)diboron (1.67 g, 6.57 mmol) dioxane (35 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.240 g, 0.292 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.46 (m, 1H),7.39 (m, 1H), 6.71 (t, J=8.2 Hz, 1H), 4.07 (t, J=5.2 Hz, 1H), 3.86 (t,J=5.2 Hz, 2H), 3.38 (t, J=5.3 Hz, 2H), 1.97 (s, 1H), 1.31 (s, 12H).

Intermediate 53: 2-fluoro-N-isopropyl-4-nitroaniline: To a solution of3,4-difluoro-nitrobenzene (4.00 g, 25.14 mmol) in ethyl acetate (40 ml)and triethylamine (3.86 ml) cooled to 0° C., isopropylamine (2.30 ml,27.65 mmol) was added slowly and stirred at room temperature for 24 h.The reaction mass quenched with water, extracted with ethylacetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:pet. ether toafford the title compound as a yellow liquid (1.80 g, 36%). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 7.94 dd, J=9.1, 1.5 Hz, 1H), 7.89 (dd, J=12.2,2.5 Hz, 1H), 6.84 (t, J=8.9 Hz, 1H), 6.78 (d, J=10.7 Hz, 1H), 3.83 (m,1H), 1.20 (d, J=6.4 Hz, 6H).

Intermediate 54: 2-fluoro-N1-isopropylbenzene-1,4-diamine: The titlecompound was obtained as a brown liquid (1.30 g, 90%) by using aprocedure that is similar to the one described for intermediate 50 fromintermediate 53 (1.70 g, 8.62 mmol), ethyl acetate (20 ml) and palladiumon charcoal (0.170 g, 5% Pd/C) which was used without purification inthe next step.

Intermediate 55: 4-bromo-2-fluoro-N-isopropylaniline: The title compoundwas obtained as a brown liquid (2.00 g, crude) by using a procedure thatis similar to the one described for intermediate 51 from intermediate 54(1.30 g, 7.73 mmol), 48% hydrobromic acid (16 ml), sodium nitrite (1.60g, 23.21 mmol), water (19 ml) and copper(I)bromide (1.66 g, 22.21 mmol)which was used without purification in the next step.

Intermediate 56:2-fluoro-N-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline:The title compound was obtained as a brown liquid (1.40 g, 58%) by usinga procedure that is similar to the one described for intermediate 12from intermediate 55 (2.00 g, 8.65 mmol), potassium acetate (2.50 g,25.97 mmol), bis(pinacolato)diboron (2.60 g, 10.38 mmol) dioxane (20 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.212 g, 0.259 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.45 (dd, J=8.1,1.2 Hz, 1H), 7.37 (dd, J=12.3, 1.2 Hz, 1H), 6.67 (t, J=8.1 Hz, 1H), 3.95(m, 1H), 3.68 (m, 1H), 1.26 (s, 12H), 1.24 (d, J=6.3 Hz, 6H).

Intermediate 57: 2-fluoro-N,N-dimethyl-4-nitroaniline: The titlecompound was obtained as a yellow liquid (2.70 g, 58%) by using aprocedure that is similar to the one described for intermediate 53 fromof 3,4-difluoro-nitrobenzene (4.00 g, 25.14 mmol) in ethyl acetate (40ml) and triethylamine (7.36 ml) and dimethylamine hydrochloride (2.25 g,27.65 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.93 (dd, J=9.1, 2.6 Hz,1H), 7.89 (dd, J=14.1, 2.6 Hz, 1H), 6.73 (t, J=9.1 Hz, 1H), 3.09 (s,6H).

Intermediate 58: 2-fluoro-N1,N1-dimethylbenzene-1,4-diamine: The titlecompound was obtained as a brown liquid (2.10 g, 93%) by using aprocedure that is similar to the one described for intermediate 50 fromintermediate 57 (2.70 g, 14.67 mmol), ethyl acetate (20 ml) andpalladium on charcoal (0.270 g, 5% Pd/C) which was used withoutpurification in the next step.

Intermediate 59: 4-bromo-2-fluoro-N,N-dimethylaniline: The titlecompound was obtained as a yellow liquid (2.20 g, 74%) by using aprocedure that is similar to the one described for intermediate 51 fromintermediate 58 (2.10 g, 13.63 mmol), 48% hydrobromic acid (26 ml),sodium nitrite (2.30 g, 40.90 mmol), water (30 ml) and copper(I)bromide(2.93 g, 20.45 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.17 (m, 2H), 6.76(t, J=8.6 Hz, 1H), 2.86 (s, 6H).

Intermediate 60:2-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline:The title compound was obtained as a yellow liquid (0.950 g, 37%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 59 (2.10 g, 9.67 mmol), potassium acetate (2.84 g,29.03 mmol), bis(pinacolato)diboron (2.94 g, 11.61 mmol), dioxane (22ml) and [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.237 g, 0.290 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.48 (dd, J=8.0, 1.4 Hz, 1H), 7.43 (dd, J=13.7, 1.4 Hz, 1H), 6.84(t, J=8.5 Hz, 1H), 2.90 (s, 6H), 1.32 (s, 12H).

Intermediate 61: 24-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine:The title compound was obtained as a off-white solid (2.00 g, 91%) byusing a procedure that is similar to the one described for intermediate12 from 4-(4-bromo-2-fluorophenyl)morpholine (1.90 g, 7.30 mmol; forpreparation see Bioorganic Med. Chem. Lett. 2006, 16, 176-180),potassium acetate (1.43 g, 14.60 mmol) bis(pinacolato)diboron (2.00 g,8.03 mmol), dioxane (48 ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.290 g,0.365 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.51 (dd, J=7.9, 1.3 Hz,1H), 7.45 (dd, J=13.5, 1.3 Hz, 1H), 6.92 (t, J=8.3 Hz, 1H), 3.87 (t,J=4.7 Hz, 4H), 3.14 (t, J=4.7 Hz, 1H), 1.32 (s, 12H).

Intermediate 62: 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine: Thetitle compound was obtained as a brown liquid (1.20 g, 31%) by using aprocedure that is similar to the one described for intermediate 51 from3-fluoro-4-(4-methylpiperazin-1-yl)aniline (3.00 g, 14.31 mmol; forpreparation see Synth. Commun. 2010, 40, 789-798), 48% hydrobromic acid(35 ml), sodium nitrite (2.96 g, 42.95 mmol), water (40 ml) andcopper(I)bromide (3.00 g, 21.47 mmol) which was used as such in nextstep.

Intermediate 63:1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine:The title compound was obtained as a brown liquid (0.450 g, 24%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 62 (1.20 g, 4.38 mmol), potassium acetate (0.86 g,8.77 mmol), bis(pinacolato)diboron (1.22 g, 4.82 mmol), dioxane (30 ml)and [1,1′-Bis (diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.179 g, 0.219 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.50 (dd, J=8.0,1.8 Hz, 1H), 7.44 (dd, J=13.4, 1.3 Hz, 1H), 6.91 (t, J=8.3 Hz, 1H), 3.23(t, J=4.7 Hz, 4H), 2.77 (t, J=4.5 Hz, 4H), 2.42 (s, 3H), 1.32 (s, 12H).

Intermediate 64: 2-(1-methoxypropylidene)malononitrile: To malononitrile(2.24 g, 33.90 mmol), trimethylorthopropionate (5.0 g, 37.26 mmol) wasadded and heated to reflux for 3 h. The reaction mixture wasconcentrated, quenched with water, extracted with ethyl acetate, driedover sodium sulphate and concentrated to afford the title compound asbrown solid (4.3 g, 93%) which was used as in a next step.

Intermediate 65: 5-amino-3-ethyl-1H-pyrazole-4-carbonitrile: To asolution of intermediate 64 (4.30 g, 31.58 mmol) in ethanol (15 ml),hydrazine hydrate (2.37 g, 47.37 mmol) was added and refluxed for 12 h.The reaction mass was concentrated under reduced pressure and to theresidue ice was added and the precipitate formed was filtered and driedunder vacuum to afford the title compound as off-white solid (2.0 g,47%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.61 (s, 1H), 5.85 (s, 2H),2.52 (q, J=7.9 Hz, 2H), 1.16 (t, J=7.6 Hz, 3H).

Intermediate 66: 3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine: Tointermediate 65 (1.00 g, 7.34 mmol), formamide (8.2 ml) was added andheated to 130° C. for 12 h. The reaction mass was quenched with waterand the solid formed was filtered, dried under vacuum to afford thetitle compound as off-white solid (0.600 g, 50%). ¹H-NMR (6 ppm,DMSO-d₆, 400 MHz): 12.90 (s, 1H), 8.07 (s, 1H), 7.09 (s, 2H), 2.95 (q,J=7.4 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).

Intermediate 67:3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The titlecompound was obtained as a light brown solid (0.600 g, 30%) by using aprocedure that is similar to the one described for intermediate 13 frombenzothiphene-2borinic acid (2.00 g, 11.23 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.95 g, 7.49 mmol),1,2-dimethoxyethane (20 ml), water (10 ml) sodium carbonate (2.30 g,22.47 mmol) and [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (1.20 g, 1.49 mmol) in microwave oven (microwavepower=100 W, temperature=100° C.) for 1 h which is used as such in nextstep.

Intermediate 68: 2-(morpholino(propylthio)methylene)malononitrile: To asolution 2-(bis(propylthio)methylene)malononitrile (1.00 g, 4.41 mmol;for preparation see J. Med. Chem. 2003, 46, 1229-1241) in ethanol (10ml), morpholine (0.384 g, 4.41 mmol) was added and refluxed for 4 h. Thereaction mass was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated to afford the title compoundas brown liquid (0.810 g, 77%) which is used as such in next step.

Intermediate 69: 5-amino-3-morpholino-1H-pyrazole-4-carbonitrile: To asolution of intermediate 68 (0.800 g, 3.37 mmol) in ethanol (8 ml),hydrazine hydrate (0.32 ml, 6.75 mmol) was added stirred at roomtemperature for 4 h. The reaction mass was concentrated and quenchedwith water, extracted with ethyl acetate, dried over sodium sulphate andconcentrated to afford the title compound as brown solid (0.450 g,69%)¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.05 (s, 1H), 6.18 (s, 2H), 3.66(t, J=4.7 Hz, 4H), 3.11 (t, J=4.7 Hz, 4H).

Intermediate 70: 3-morpholino-1H-pyrazolo[3,4-d]pyrimidin-4-amine: Tointermediate 69 (0.450 g, 2.32 mmol), formamide (4 ml) was added andheated to 130° C. for 12 h. The reaction mass was quenched with water,extracted with ethyl acetate, dried over sodium sulphate andconcentrated The crude product was purified by column chromatographywith methanol:ethyl acetate to afford the title compound as off-whitesolid (0.200 g, 39%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.56 (s, 1H),8.08 (s, 1H), 6.86 (s, 2H), 3.79 (t, J=4.5 Hz, 4H), 3.07 (t, J=4.6 Hz,4H).

Intermediate 71: 2-((dimethylamino)(propylthio)methylene)malononitrile:The title compound was obtained as a brown liquid (0.830 g, 96%) byusing a procedure that is similar to the one described for intermediate68 from 2-(bis(propylthio)methylene)malononitrile (1.00 g, 4.41 mmol) inethanol (10 ml), dimethylamine hydrochloride (0.360 g, 4.41 mmol) andtriethylamine (0.446 g, 4.41 mmol) which was used as such in next step.

Intermediate 72: 5-amino-3-(dimethylamino)-1H-pyrazole-4-carbonitrile:The title compound was obtained as a brown solid (0.510 g, 71%) by usinga procedure that is similar to the one described for intermediate 69from intermediate 71 (0.930 g, 4.76 mmol), ethanol (10 ml) and hydrazinehydrate (0.46 ml, 9.52 mmol) which was used as such in next step.

Intermediate 73:N3,N3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine-3,4-diamine: The titlecompound was obtained as a brown solid (0.280 g, 47%) by using aprocedure that is similar to the one described for intermediate 70 fromintermediate 72 (0.510 g, 3.37 mmol) and formamide (5 ml). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 12.37 (s, 1H), 8.04 (s, 1H), 6.88 (s, 2H), 2.76(s, 6H).

Intermediate 74: 2-(piperidin-1-yl(propylthio)methylene)malononitrile:The title compound was obtained as a brown liquid (0.840 g, 60%) byusing a procedure that is similar to the one described for intermediate68 from 2-(bis(propylthio)methylene)malononitrile (1.00 g, 4.41 mmol) inethanol (10 ml), piperidine (0.376 g, 4.41 mmol). ¹H-NMR (δ ppm, CDCl₃,400 MHz): 3.79 (t, J=5.0 Hz, 4H), 3.01 (t, J=7.2 Hz, 2H), 1.74 (m, 6H),1.72 (m, 2H), 1.06 (t, J=7.3 Hz, 3H).

Intermediate 75: 5-amino-3-(piperidin-1-yl)-1H-pyrazole-4-carbonitrile:The title compound was obtained as a brown liquid (0.500 g, 73%) byusing a procedure that is similar to the one described for intermediate69 from intermediate 74 (0.840 g, 3.56 mmol), ethanol (10 ml) andhydrazine hydrate (0.40 ml, 8.27 mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 10.92 (s, 1H), 6.09 (s, 1H), 3.12 (m, 4H), 1.53 (m, 6H).

Intermediate 76: 3-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a brown solid (0.600 g, 95%) by usinga procedure that is similar to the one described for intermediate 70from intermediate 75 (0.550 g, 2.87 mmol) and formamide (5 ml). ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 12.44 (s, 1H), 8.07 (s, 1H), 6.69 (s, 2H),3.05 (t, J=5.1 Hz, 4H), 1.69 (m, 4H), 1.54 (m, 2H).

Intermediate 77: 2-(propylthio(pyrrolidin-1-yl)methylene)malononitrile:The title compound was obtained as a brown liquid (0.950 g, 97%) byusing a procedure that is similar to the one described for intermediate68 from 2-(bis(propylthio)methylene)malononitrile (1.00 g, 4.41 mmol) inethanol (10 ml), pyrrolidine (0.314 g, 4.41 mmol) which was used as suchin next step.

Intermediate 78: 5-amino-3-(pyrrolidin-1-yl)-1H-pyrazole-4-carbonitrile:The title compound was obtained as a brown liquid (0.640 g, 84%) byusing a procedure that is similar to the one described for intermediate69 from intermediate 77 (0.950 g, 4.29 mmol), ethanol (10 ml) andhydrazine hydrate (0.42 ml, 8.58 mmol) which was used as such in nextstep.

Intermediate 79:3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: The titlecompound was obtained as a brown solid (0.350 g, 29%) by using aprocedure that is similar to the one described for intermediate 70 fromintermediate 78 (0.640 g, 3.61 mmol) and formamide (6 ml). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 12.28 (s, 1H), 8.02 (s, 1H), 6.79 (s, 2H), 3.32(t, J=6.6 Hz, 4H), 1.89 (m, 4H).

Intermediate 80: 1-benzhydryl-3-(4-bromo-2-fluorophenoxy)azetidine: Thetitle compound was obtained as a colourless liquid (0.631 g, 30%) byusing a procedure that is similar to the one described for intermediate47 from 4-bromo-2-fluorophenol (1.00 g, 5.23 mmol) in THF (12 ml),1-benzhydrylazetidin-3-ol (1.25 g, 5.23 mmol) andtris(4-methoxyphenyl)phosphine (2.70 g, 7.85 mmol) anddiisopropylazodicarboxylate (1.60 ml, 7.85 mmol). ¹H-NMR (δ ppm, CDCl₃,400 MHz): 7.42 (m, 4H), 7.29-7.17 (m, 7H), 7.11 (m, 1H), 6.59 (t, J=8.8Hz, 1H), 4.80 (quintet, J=5.8 Hz, 1H), 4.43 (s, 1H), 3.72 (dd, J=6.1,2.0 Hz, 2H), 3.17 (dd, J=5.7, 1.9 Hz, 2H).

Intermediate 81:1-benzhydryl-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine:The title compound was obtained as a off-white solid (0.850 g, 76%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 80 (1.00 g, 2.42 mmol), potassium acetate (0.713 g,7.27 mmol), bis(pinacolato)diboron (0.738 g, 2.90 mmol) dioxane (10 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.059 g, 0.072 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.49 (dd, J=11.0,1.3 Hz, 1H), 7.42 (m, 4H), 7.29 (m, 5H), 7.21 (m, 2H), 6.68 (t, J=8.1Hz, 1H), 4.86 (quintet, J=5.9 Hz, 1H), 4.44 (s, 1H), 3.74 (dd, J=6.1,1.9 Hz, 2H), 3.19 (dd, J=5.8, 1.9 Hz, 2H), 1.31 (s, 12H).

Intermediate 82: 3-(4-bromo-2-fluorophenoxy)oxetane: The title compoundwas obtained as a brown solid (0.900 g, 54%) by using a procedure thatis similar to the one described for intermediate 47 from4-bromo-2-fluorophenol (1.28 g, 6.74 mmol) in THF (6 ml),3-hydroxyoxetane (0.500 g, 6.74 mmol) and triphenylphosphine (2.65 g,10.12 mmol) and diisopropylazodicarboxylate (1.99 ml, 10.12 mmol).¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.28 (dd, J=12.9, 2.4 Hz, 1H), 7.17 (m,1H), 6.52 (t, J=8.7 Hz, 1H), 5.20 (m, 1H), 4.96 (dd, J=8.0, 7.0 Hz, 2H),4.82 (dd, J=6.3, 5.3 Hz, 2H).

Intermediate 83:2-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:The title compound was obtained as a brown liquid (0.800 g, 80%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 82 (0.900 g, 3.64 mmol), potassium acetate (1.00 g,10.92 mmol), bis(pinacolato)diboron (1.10 g, 4.37 mmol) dioxane (10 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.090 g, 0.109 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.53 (dd, J=11.8,1.4 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 6.58 (t, J=8.0 Hz, 1H), 5.27 (m,1H), 4.98 (dd, J=7.7, 6.9 Hz, 2H), 4.83 (dd, J=7.9, 5.3 Hz, 2H), 1.32(s, 12H).

Intermediate 84:3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: Thetitle compound was obtained as a pale yellow solid (0.143 g, 52%) byusing a procedure that is similar to the one described for intermediate13 from 4-isopropoxy-3-methylphenylboronic acid (0.241 g, 1.24 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.957 mmol), DMF(1.5 ml), ethanol (0.6 ml), water (0.6 ml), sodium carbonate (0.304 g,2.87 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047mmol) in microwave oven (microwave power=100 W, temperature=100° C.) for3 h. Mass: 284.1 (M⁺+1).

Intermediate 85:2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine:The title compound was obtained as a brown liquid (0.400 g, 65%) byusing a procedure that is similar to the one described for intermediate12 from 5-bromo-2-isopropoxypyrimidine (0.500 g, 2.30 mmol forpreparation see Organic. Lett. 2010, 12, 4478-4481.), potassium acetate(0.678 g, 6.91 mmol), bis(pinacolato)diboron (0.702 g, 2.76 mmol)dioxane (5 ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.056 g, 0.069 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 8.77 (s, 2H), 5.35 (m, 1H), 1.39 (d, J=6.1 Hz, 6H), 1.33 (s, 12H).

Intermediate 86:3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: Thetitle compound was obtained as a pale yellow solid (0.095 g, 20%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 61 (0.393 g, 1.505 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 2.25 mmol), DMF(2.5 ml), ethanol (1.5 ml), water (1.0 ml), sodium carbonate (0.478 g,4.51 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.087 g, 0.075mmol) in microwave oven (microwave power=100 W, temperature=100° C.) for2 h. Mass: 315.0 (M⁺+1).

Intermediate 87: 2-acetyl-3-fluorophenyl butyrate: Pyridine (7.2 ml) andpropionyl chloride (3.85 g, 41.65 mmol) were added to an ice-cold To asolution of intermediate 4 (5.00 g, 32.43 mmol) in dichloromethane (750ml), butyric acid (2.85 g, 32.43 mmol), dicyclohexylcarbodiimide (6.67g, 32.43 mmol) and 4-dimethylaminopyridine (0.79 g, 6.48 mmol) wereadded and stirred at room temperature for 12 h. The reaction mixture wasfiltered, washed with dichloromethane and concentrated. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as a yellow liquid(2.80 g, 39%0 which was used as such in next step.

Intermediate 88: 5-fluoro-2-propyl-4H-chromen-4-one: To a solution of 87(2.8 g, 12.55 mmol) in DMSO (15 ml) cooled to 0° C., sodium hydride(0.301 g, 12.55 mmol) was added maintained at the same temperature for 1h. The mixture was warmed to RT and stirred for 12 h. The reaction wasquenched by the addition of 2N HCl and extracted with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulphate and thesolvents removed. The crude product was dissolved in dioxane (6 ml) andsulphuric acid (8 ml) was added and heated to 100° C. for 12 h. Aqueoussodium bicarbonate solution was added to the mixture and extracted withethyl acetate. The organic layer was washed with water, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as yellow liquid(1.6 g, 62%) which was used as such in next step.

Intermediate 89: 3-bromo-5-fluoro-2-propyl-4H-chromen-4-one: To asolution of intermediate 88 (1.50 g, 7.27 mmol) in DMF (9 ml),N-bromosuccinimide (1.29 g, 7.27 mmol) was added at RT. After 12 h, thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulphate and the solvent removed to afford the title compound asoff-white solid (1.60 g, 77%) which was used as such in next step.

Intermediate 90: 5-fluoro-3-phenyl-2-propyl-4H-chromen-4-one: The titlecompound was obtained as a off-white solid (1.10 g, 69%) by using aprocedure that is similar to the one described for intermediate 21 fromintermediate 89 (1.60 g, 5.61 mmol), phenylboronic acid (1.09 g, 8.97mmol), dioxan (18 ml), potassium carbonate (2.32 g, 16.83 mmol), water(5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.388 g, 0.336mmol). Mass: 283.4 (M⁺+1).

Intermediate 91: 2-(1-bromopropyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as a off-white solid (1.3 g, 925%) byusing a procedure that is similar to the one described for intermediate22 from intermediate 90 (1.10 g, 3.89 mmol), carbon tetrachloride (22ml) N-bromosuccinimide (0.69 g, 3.89 mmol) and azobisisobutyronitrile(42 mg). Mass: 362.8 (M++1).

Intermediate 92:2-(1-(5-fluoro-4-oxo-3-phenyl-4H-chromen-2-yl)propyl)isoindoline-1,3-dione:To a solution of potassium phthalimide (0.97 g, 5.23 mmol) in DMF (10ml), intermediate 91 (2.0 g, 3.49 mmol) was added and stirred for 12 h.The reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetatel:pet. ether to afford the titlecompound as a off-white solid (1.0 g, 67%). Mass: 428.1 (M⁺+1).

Intermediate 93: 2-(1-aminopropyl)-5-fluoro-3-phenyl-4H-chromen-4-one:To a solution of intermediate 92 (0.50 g, 1.16 mmol) in methanol (5 ml),hydrazine hydrate (0.087 g, 1.75 mmol) was added and refluxed for 3 h.The reaction mass cooled, filtered and washed with chloroform andconcentrated. The crude product was purified by column chromatographywith dichloromethane:methanol to afford the title compound as aoff-white solid (0.34 g, 98%). Mass: 297.1 (M⁺).

Intermediate 94: N-(4-bromo-2-fluorophenyl)isobutyramide: To a solutionof 4-bromo-2-fluoroaniline (2.0 g, 10.51 mmol) in dichloromethane (20ml) cooled to 0° C., triethylamine (2.90 ml, 21.02) was added followedby isobutyryl chloride (1.20 ml, 12.61 mol). After stirring at roomtemperature for 8 h, the reaction mixture was quenched with water,extracted with dichloromethane, dried over sodium sulphate andconcentrated to afford the title compound as a off-white solid (2.60 g,96%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.29 (t, J=8.4 Hz, 1H), 7.31 (brs, 1H), 7.27 (m, 2H), 2.59 (quintet, J=6.9 Hz, 1H), 1.27 (d, J=6.9 Hz,6H).

Intermediate 95:N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isobutyramide:The title compound was obtained as a off-white solid (0.900 g, 77%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 94 (1.00 g, 3.84 mmol), potassium acetate (0.750 g,7.68 mmol), bis(pinacolato)diboron (1.07 g, 4.22 mmol) dioxane (15 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.62 g, 0.768 mmol) which was used as such in next step.

Intermediate 96: N-(4-bromo-2-fluorophenyl)acetamide: To a solution of4-bromo-2-fluoroaniline (2.0 g, 10.51 mmol) in dichloromethane (20 ml)cooled to 0° C., triethylamine (2.90 ml, 21.02) was added followed byacetyl chloride (0.90 ml, 12.61 mol). After stirring at room temperaturefor 8 h, the reaction mixture was quenched with water, extracted withdichloromethane, dried over sodium sulphate and concentrated to affordthe title compound as a off-white solid (2.60 g, 99%) which was used assuch in next step.

Intermediate 97:N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide:The title compound was obtained as a off-white solid (0.800 g, 67%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 96 (1.00 g, 4.30 mmol), potassium acetate (0.840 g,8.61 mmol), bis(pinacolato)diboron (1.20 g, 4.74 mmol) dioxane (15 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.70 g, 0.861 mmol) which was used as such in next step.

Intermediate 98:3-iodo-N,N-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine: To a solutionof N,N-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 3.06 mmolfor preparation see J. Amer. Chem. Soc. 1956, 784-790.) in DMF (4 ml),N—Iodosuccinimide (1.00 g, 4.59 mmol) was added and stirred at 80° C.for 22 h. The reaction mixture was quenched with water, extracted withethyl acetate, dried over sodium sulphate and concentrated to afford thetitle compound as a brown solid (0.460 g, 46%) which was used as such innext step.

Intermediate 99:3-(3-fluoro-4-isopropoxyphenyl)-N,N-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a light brown solid (0.220 g, 50%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 12 (0.581 g, 2.07 mmol), intermediate 98 (0.400 g,1.38 mmol), DMF (3 ml), ethanol (1.5 ml), water (1.5 ml) sodiumcarbonate (0.440 g, 4.15 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.069 mmol). Mass:316.3 (M++1).

Intermediate 100: 3-iodo-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.10 g,7.37 mmol, for preparation see J. Amer. Chem. Soc. 1956, 784-790) in DMF(8 ml), N-Iodosuccinimide (2.48 g, 11.06 mmol) was added and stirred at80° C. for 12 h. The reaction mixture was quenched with water, extractedwith ethyl acetate, dried over sodium sulphate and concentrated toafford the title compound as a brown solid (0.970 g, 48%). Mass: 275.9(M++1).

Intermediate 101:5-fluoro-3-(3-fluorophenyl)-2-(1-(3-iodo-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a light brown solid (0.230 g, 32%) byusing a procedure that is similar to the one described for intermediate34 from intermediate 22 (0.650 g, 1.78 mmol), intermediate 100 (0.350 g,1.27 mmol), DMF (3 ml) and potassium carbonate (0.175 g, 1.27 mmol).Mass: 560.1 (M++1).

Intermediate 102: 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine: To asolution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.00 g, 12.97 mmol)in Dioxan (20 ml), morpholine 5.65 g, 64.86 mmol) was added and refluxedfor 2 h. The reaction mixture was quenched with water, filtered anddried under vacuum to afford the title compound as a brown solid (2.40g, 90%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 12.49 (s, 1H), 8.33 (s, 1H),7.94 (s, 1H), 3.95 (t, J=4.6 Hz, 4H), 3.83 (t, J=5.2 Hz, 4H).

Intermediate 103: 4-(3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine:To a solution of intermediate 102 (1.50 g, 7.31 mmol) in DMF (12 ml),N-Iodosuccinimide (2.46 g, 10.97 mmol) was added and stirred at 80° C.for 22 h. The reaction mixture was quenched with water, filtered, washedwith pet. ether and dried under vacuum to afford the title compound as abrown solid (1.90 g, 79%). ¹H-NMR (δ ppm, DMSO-D6, 400 MHz): 14.06 (s,1H), 8.34 (s, 1H), 3.78 (t, J=5.0 Hz, 4H), 3.73 (t, J=5.0 Hz, 4H).

Intermediate 104:4-(3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine:The title compound was obtained as a light brown solid (0.180 g, 33%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 12 (0.634 g, 2.26 mmol), intermediate 103 (0.500 g,1.51 mmol), DMF (4 ml), ethanol (2.0 ml), water (2.0 ml) sodiumcarbonate (0.480 g, 4.53 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol). Mass:357.38 (M++1).

Intermediate 105:5-fluoro-3-(4-fluorophenyl)-2-(1-(3-iodo-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a light brown solid (0.350 g, 53%) byusing a procedure that is similar to the one described for intermediate34 from intermediate 31 (0.734 g, 2.11 mmol), intermediate 103 (0.350 g,1.05 mmol), DMF (4 ml) and cesium carbonate (0.343 g, 1.05 mmol). Mass:616.2 (M++1).

Intermediate 106:5-fluoro-3-(3-fluorophenyl)-2-(1-(3-iodo-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.400 g, 54%) byusing a procedure that is similar to the one described for intermediate34 from intermediate 22 (0.629 g, 1.81 mmol), intermediate 103 (0.400 g,1.20 mmol), DMF (4 ml) and potassium carbonate (0.167 g, 1.20 mmol).Mass 616.2 (M++1).

Intermediate 107:2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-bromo-5-fluoro-4H-chromen-4-one:The title compound was obtained as a brown solid (0.650 g, 68%) by usinga procedure that is similar to the one described for intermediate 27from intermediate 39 (0.500 g, 1.69 mmol), potassium carbonate (0.46 g,3.38 mmol), DMF (10 ml) and intermediate 28 (0.82 g, 2.37 mmol) whichwas used as such for next step.

Intermediate 108:2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as a pale brown solid (2.00 g, 64%) byusing a procedure that is similar to the one described for intermediate34 from intermediate 33 (2.10 g, 6.01 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.13 g, 12.02 mmol), DMF(8.4 ml) and cesium carbonate (3.91 g, 12.02 mmol) which was used as innext step.

Intermediate 109:5-fluoro-3-(4-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: Thetitle compound was obtained as a pale brown solid (3.50 g, 78%) by usinga procedure that is similar to the one described for intermediate 23from intermediate 31 (5.50 g, 15.01 mmol), DMSO (55 ml) and n-butanol(2.75 ml). Mass: 303.1 (M++1).

Intermediate 110: 5-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one:The title compound was obtained as a pale brown solid (2.60 g, 60%) byusing a procedure that is similar to the one described for intermediate23 from intermediate 33 (5.30 g, 15.26 mmol), DMSO (40 ml) and n-butanol(2.20 ml). Mass: 284.8 (M⁺).

Intermediate 111: 2-acetyl-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a pale yellow solid (2.20 g, 64%) byusing a procedure that is similar to the one described for intermediate24 from intermediate 109 (3.50 g, 11.54 mmol), DMSO (3.27 ml, 46.16mmol), dichloromethane (50 ml), oxalyl chloride (1.99 ml, 23.08 mmol)and triethylamine (7 ml) which was used as such in next step.

Intermediate 112: 2-acetyl-5-fluoro-3-phenyl-4H-chromen-4-one: The titlecompound was obtained as a pale yellow solid (1.80 g, 63%) by using aprocedure that is similar to the one described for intermediate 24 fromintermediate 110 (2.50 g, 8.76 mmol), DMSO (2.48 ml, 35.05 mmol),dichloromethane (42 ml), oxalyl chloride (1.51 ml, 17.52 mmol) andtriethylamine (5.5 ml) which was used as such in next step.

Intermediate 113:(R)/(S)-5-fluoro-3-(4-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one:To a solution of intermediate 111 (0.568 g, 1.89 mmol) in DMF (4 ml)under nitrogen purging, formic acid:trietylamine 5:2 azeotrope (1 ml)was added followed by [(S,S)tethTsDpenRuCl] (3 mg). The reaction mixturewas heated at 80° C. for 1.5 h under continuous nitrogen purging. Thereaction mixture was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (0420 g, 74%).Enantiomeric excess: 74%, enriched in the late eluting isomer (retentiontime: 9.24 min. as determined by HPLC on a chiralpak AD-H column.

Intermediate 114:(R)/(S)-5-fluoro-3-(4-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one:To a solution of intermediate 111 (0.568 g, 1.89 mmol) in DMF (4 ml)under nitrogen purging, formic acid:trietylamine 5:2 azeotrope (1 ml)was added followed by [(R,R)tethTsDpenRuCl] (3 mg). The reaction mixturewas heated at 80° C. for 1.5 h under continuous nitrogen purging. Thereaction mixture was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (0430 g, 75%).Enantiomeric excess: 74%, enriched in the fast eluting isomer (retentiontime: 7.75 min. as determined by HPLC on a chiralpak AD-H column.

Intermediate 115:(R)/(S)-5-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one: To asolution of intermediate 112 (0.568 g, 1.89 mmol) in DMF (4 ml) undernitrogen purging, formic acid:trietylamine 5:2 azeotrope (1 ml) wasadded followed by [(S,S)tethTsDpenRuCl] (3 mg). The reaction mixture washeated at 80° C. for 1.5 h under continuous nitrogen purging. Thereaction mixture was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (0.380 g, 66%).Enantiomeric excess: 64%, enriched in the late eluting isomer (retentiontime: 8.85 min. as determined by HPLC on a chiralpak AD-H column.

Intermediate 116:(R)/(S)-5-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one: To asolution of intermediate 112 (0.568 g, 1.89 mmol) in DMF (4 ml) undernitrogen purging, formic acid:trietylamine 5:2 azeotrope (1 ml) wasadded followed by [(R,R)tethTsDpenRuCl] (3 mg). The reaction mixture washeated at 80° C. for 1.5 h under continuous nitrogen purging. Thereaction mixture was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (0.410 g, 72%).Enantiomeric excess: 64%, enriched in the fast eluting isomer (retentiontime: 7.43 min. as determined by HPLC on a chiralpak AD-H column.

Intermediate 117:3-(3-fluoro-4-morpholinophenyl)-N,N-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a pale brown solid (0.340 g, 36%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 61 (1.27 g, 4.15 mmol), intermediate 98 (0.800 g,2.76 mmol), DMF (6 ml), ethanol (3 ml), water (3 ml), sodium carbonate(0.880 g, 8.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.160g, 0.138 mmol) in microwave oven (microwave power=100 W,temperature=100° C.) for 2 h. Mass: 343.1 (M++1).

Intermediate 118:3-(3-fluoro-4-morpholinophenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a off-white solid (0.350 g, 29%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 61 (1.67 g, 5.45 mmol), intermediate 100 (1.00 g,3.63 mmol), DMF (7 ml), ethanol (3.5 ml), water (3.5 ml), sodiumcarbonate (1.15 g, 10.89 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.209 g, 0.181 mmol) inmicrowave oven (microwave power=100 W, temperature=100° C.) for 2 h.Mass: 329.2 (M⁺+1).

Intermediate 119:3-(3-fluoro-4-isopropoxyphenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine:The title compound was obtained as a brown solid (0.205 g, 19%) by usinga procedure that is similar to the one described for intermediate 13from intermediate 12 (1.52 g, 5.45 mmol), intermediate 100 (1.00 g, 3.63mmol), DMF (7 ml), ethanol (3.5 ml), water (3.5 ml), sodium carbonate(1.15 g, 10.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.209g, 0.181 mmol) in microwave oven (microwave power=100 W,temperature=100° C.) for 2 h. Mass: 301.9 (M⁺).

Intermediate 120: 4-(2-chloro-4-nitrophenyl)morpholine: The titlecompound was obtained as a yellow liquid (6.70 g, 53%) by using aprocedure that is similar to the one described for intermediate 53 fromof 3,4-dichloro-nitrobenzene (10.00 g, 52.08 mmol) in ethyl acetate (83ml) and triethylamine (7.99 ml) and morpholine (4.99 g, 57.29 mmol).¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.25 (d, J=2.6 Hz, 1H), 8.12 (dd,J=8.5, 2.6 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.90 (t, J=4.5 Hz, 1H), 3.22(t, J=4.6 Hz, 1H).

Intermediate 121: 3-chloro-4-morpholinoaniline: To a solution ofintermediate 120 (6.00 g, 24.72 mmol) in ethanol (60 ml) and water (30ml), iron (6.89 g, 123.60 mmol) and ammonium chloride (2.64 g, 49.44mmol) were added and refluxed for 3 h. The reaction mixture was filteredthrough celite, washed with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure to affordthe title compound was obtained as a brown solid (5.50 g) which was usedwithout purification in the next step.

Intermediate 122: 4-(4-bromo-2-chlorophenyl)morpholine: The titlecompound was obtained as a brown liquid (5.20 g, 72%) by using aprocedure that is similar to the one described for intermediate 51 fromintermediate 121 (5.50 g, 25.85 mmol), 48% hydrobromic acid (64 ml),sodium nitrite (5.35 g, 77.57 mmol), water (73 ml) and copper(I)bromide(5.56 g, 38.78 mmol) which was used without purification in the nextstep.

Intermediate 123:4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine:The title compound was obtained as a colourless liquid (2.00 g, 89%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 122 (2.00 g, 7.23 mmol), potassium acetate (1.41 g,14.46 mmol), bis(pinacolato)diboron (2.01 g, 7.95 mmol), dioxane (15 ml)and [1,1′-Bis (diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.290 g, 0.360 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.80 (d, J=1.4Hz, 1H), 7.66 (dd, J=8.0, 1.4 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 3.89 (t,J=4.4 Hz, 4H), 3.12 (t, J=4.5 Hz, 4H), 1.33 (s, 12H).

Intermediate 124: 4-bromo-2-chloro-1-isopropoxybenzene: The titlecompound was obtained as a colourless liquid (5.60 g, 93%) by using aprocedure that is similar to the one described for intermediate 47 from4-bromo-2-chlorophenol (5.00 g, 24.10 mmol) in THF (50 ml), isopropanol(1.85 ml, 24.10 mmol), triphenylphosphine (9.48 g, 36.51 mmol) anddiisopropylazodicarboxylate (7.10 ml, 36.51 mmol) which was used as suchin next step.

Intermediate 125:2-(3-chloro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:The title compound was obtained as a yellow liquid (6.50 g, 99%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 124 (6.00 g, 24.04 mmol), potassium acetate (4.71g, 48.08 mmol), bis(pinacolato)diboron (6.71 g, 26.44 mmol) dioxane (95ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.980 g, 12.02 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 7.79 (d, J=1.4 Hz, 1H), 7.63 (dd, J=8.2, 1.4 Hz, 1H), 6.92 (d,J=8.2 Hz, 1H), 4.64 (quintet, J=6.1 Hz, 1H), 1.38 (d, J=6.1 Hz, 6H),1.25 (s, 12H).

Intermediate 126: 6-bromo-2-methylbenzo[d]oxazole: To2-amino-5-bromophenol (1.00 g, 5.32 mmol), acetic acid ((0.006 ml) andtriethylorthoacetate (1.75 ml, 9.58 mmol) were added and refluxed for 30min. The reaction mixture was quenched with water, extracted with ethylacetate, dried over sodium sulphate and concentrated. The crude productwas column chromatographed with ethyl acetate:petroleum ether to affordthe title compound as a orange solid ((0.756 g, 65%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): δ 7.64 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.43(dd, J=8.4, 1.7 Hz, 1H), 2.67 (s, 3H).

Intermediate 127:2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole:The title compound was obtained as a orange solid (0.965 g, 88%) byusing a procedure that is similar to the one described for intermediate12 from intermediate 126 (0.900 g, 4.24 mmol), potassium acetate (0.833g, 8.48 mmol), bis(pinacolato)diboron (1.18 g, 4.66 mmol) dioxane (10ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.173 g, 0.212 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 7.90 (s, 1H), 7.76 (dd, J=7.8, 0.5 Hz, 1H), 7.64 (d, J=7.9 Hz,1H), 2.64 (s, 3H), 1.36 (s, 12H).

Intermediate 128:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one: Thetitle compound was obtained as a off-white solid (0.850 g, 39%) by usinga procedure that is similar to the one described for intermediate 12from 6-bromoisoindolin-1-one (1.00 g, 4.71 mmol for preparation see J.Pharm. Science & Technol. 2010,2, 380-390.), potassium acetate (1.60 g,16.50 mmol), bis(pinacolato)diboron (1.30 g, 5.18 mmol) dioxane (18 ml)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.190 g, 0.235 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.36 (s, 1H),8.00 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 6.55 (s, 1H), 4.46 (s,2H), 1.35 (s, 12H).

Intermediate 129:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one: Thetitle compound was obtained as a off-white solid (0.410 g, 84%) by usinga procedure that is similar to the one described for intermediate 12from 5-bromoisoindolin-1-one (0.400 g, 1.88 mmol), potassium acetate(0.645 g, 6.58 mmol), bis(pinacolato)diboron (0.520 g, 2.07 mmol)dioxane (7 ml) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.076 g, 0.094 mmol). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 7.93 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 7.16 (s, 1H), 1H), 4.45(s, 2H), 1.36 (s, 12H).

Intermediate 130:1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone:The title compound was obtained as a colourless liquid (1.50 g, 82%) byusing a procedure that is similar to the one described for intermediate12 from 1-(4-bromo-2-fluorophenyl)ethanone (1.50 g, 6.91 mmol),potassium acetate (1.35 g, 13.82 mmol), bis(pinacolato)diboron (1.92 g,7.60 mmol) dioxane (30 ml) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.282 g, 0.345 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.84 (t, J=7.5Hz, 1H), 7.62 (dd, J=7.6, 0.6 Hz, 1H), 7.55 (d, J=11.0 Hz, 1H), 2.62 (d,J=4.8 Hz, 3H), 1.35 (s, 12H).

Intermediate 131:3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: Thetitle compound was obtained as a pale brown solid (0.250 g, 20%) byusing a procedure that is similar to the one described for intermediate13 from intermediate 123 (1.87 g, 5.74 mmol),3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmol), DMF (6.4ml), ethanol (2.1 ml), water (1.4 ml), sodium carbonate (1.21 g, 11.49mmol) and tetrakis(triphenylphosphine)palladium(0) (0.220 g, 0.190 mmol)in microwave oven (microwave power=100 W, temperature=100° C.) for 1 h.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): 13.57 (s, 1H), 8.20 (s, 1H), 7.66 (d,J=1.9 Hz, 1H), 7.59 (dd, J=8.2, 1.9 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H),6.79 (s, 2H), 3.77 (t, J=4.3 Hz, 4H), 3.05 (t, J=4.3 Hz, 4H).

Intermediate 132:N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide:The title compound was obtained as a off-white solid (1.00 g, 84%) byusing a procedure that is similar to the one described for intermediate12 from N-(3-bromophenyl)methanesulfonamide (1.00 g, 3.99 mmol),potassium acetate (0.78 g, 7.98 mmol), bis(pinacolato)diboron (1.11 g,4.39 mmol) dioxane (10 ml) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.162 g, 0.199 mmol). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): 9.66 (s, 1H),7.51 (d, J=1.3 Hz, 1H), 7.41 (dd, J=5.2, 0.9 Hz, 1H), 7.35 (m, 2H), 2.94(s, 3H), 1.28 (s, 12H).

Intermediate 133: 2-ethyl-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a brown solid (0.500 g, 47%) by usinga procedure that is similar to the one described for intermediate 21from intermediate 20 (1.00 g, 3.68 mmol), 2-fluorophenylboronic acid(0.820 g, 5.90 mmol), dioxan (6 ml), potassium carbonate (1.50 g, 11.04mmol), water (1.0 ml) and tetrakis(triphenylphosphine)palladium(0)(0.255 g, 0.220 mmol). Mass: 287.3 (M⁺+1).

Intermediate 134:2-(1-bromoethyl)-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one: The titlecompound was obtained as a brown solid (0.510 g, 78%) by using aprocedure that is similar to the one described for intermediate 22 fromintermediate 133 (0.500 g, 1.74 mmol), carbon tetrachloride (13 ml)N-bromosuccinimide (0.309 g, 1.74 mmol) and azobisisobutyronitrile (30mg) which was used as such for next step.

Intermediate 135:5-fluoro-3-(2-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one: Thetitle compound was obtained as a pale brown solid (0.210 g, 50%) byusing a procedure that is similar to the one described for intermediate23 from intermediate 134 (0.500 g, 1.36 mmol), DMSO (5 ml) and n-butanol(1 ml). Mass: 302.8 (M+).

Intermediate 136: 5-fluoro-3-(3-fluorophenyl)-2-propyl-4H-chromen-4-one:The title compound was obtained as a pale yellow solid (2.60 g, 69%) byusing a procedure that is similar to the one described for intermediate21 from intermediate 89 (2.80 g, 9.89 mmol), 3-fluorophenylboronic acid(2.20 g, 15.82 mmol), dioxan (18 ml), potassium carbonate (4.10 g, 29.67mmol), water (2.6 ml) and tetrakis(triphenylphosphine)palladium(0)(0.685 g, 0.593 mmol) which was used as such in next step.

Intermediate 137:2-(1-bromopropyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: Thetitle compound was obtained as a brown solid (2.95 g, 89%) by using aprocedure that is similar to the one described for intermediate 22 fromintermediate 136 (2.60 g, 9.21 mmol), carbon tetrachloride (25 ml)N-bromosuccinimide (1.64 g, 9.21 mmol) and azobisisobutyronitrile (0.247g) which was used as such in next step.

Intermediate 138: 2-fluoro-9-trityl-9H-purin-6-amine: To a solution of2-fluoro-9H-purin-6-amine (0.50 g, 3.26 mmol) in DMF (3 ml), pyridine(0.5 ml) followed by trityl chloride (1.00 g, 3.91 mmol). After stirringat room temperature for 12, the reaction mass was quenched with water,the precipitate formed was filtered, washed with water and dried undervacuum to afford the title compound as off-white solid (1.20 g, 93%)which was used as such in next step.

Intermediate 139: N,N-Diboc-2-fluoro-9-trityl-9H-purin-6-amine: To asolution of intermediate 138 (1.10 g, 2.78 mmol) in THF (11 ml) cooledto 0° C., boc-anhydride (1.40 ml, 6.12 mmol) and 4-dimethylaminopyridine(0.034 g, 0.278 mmol0 were added and stirred at room temperature for 15h. The reaction mass was quenched with water, extracted with ethylacetate, dried over sodium sulphate and concentrated under vacuum toafford the title compound as off-white solid (1.60 g, 97%) which wasused as such in next step.

Intermediate 140: tert-butyl 2-methoxy-9-trityl-9H-purin-6-ylcarbamate:To a solution of intermediate 139 (1.50 g, 2.51 mmol) in methanol (6ml), potassium carbonate (0.34 g, 2.51 mmol) was added and heated to 90°C. for 2 h. The reaction mass was concentrated quenched with water,extracted with ethyl acetate, dried over sodium sulphate andconcentrated under vacuum. The crude product was column chromatographedwith ethyl acetate:petroleum ether to afford the title compound asoff-white solid (0.255 gg, 20%). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): 10.00(s, 1H), 7.89 (s, 1H), 7.89 (m, 9H), 7.19 (m, 6H), 3.33 (s, 3H), 1.44(s, 9H).

Intermediate 141:(S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethylmethanesulfonate: To a cooled solution of intermediate 23a (0.800 g,2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) was added stirredat room temperature for 2 h. The reaction mass was quenched with water,extracted with dichloromehane, dried over sodium sulphate andconcentrated to afford the title compound as brown solid (1.00 g, 100%)which was used as such in next step

Intermediate 142:(S)/(R)-2-(1-azidoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 141 (0.900 g, 2.36 mmol) in DMF (18 ml),sodium azide (0.306 g, 4.72 mmol) was added heated to 60° C. After 2 h,reaction mass was quenched with water, extracted with dichloromehane,dried over sodium sulphate and concentrated. The crude product wascolumn chromatographed with ethyl acetate:petroleum ether to afford thetitle compound as brown liquid (0.650 g, 84%) which was used as such innext step.

Intermediate 143: (S)/(R)-22-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To asolution of intermediate 142 (0.600 g, 1.82 mmol) in THF (2.4 ml) andwater (1.2 ml), triphenylphosphine (0.455 g, 1.73 mmol) was addedstirred at room temperature for 14 h. The reaction mass was quenchedwith water, extracted with ethyl acetate, dried over sodium sulphate andconcentrated. The crude product was column chromatographed withmethanol:dichloromethane to afford the title compound as brown liquid(0.300 g, 55%) which was used as such in next step.

Intermediate 144: 2-methoxy-6-methylbenzaldehyde oxime: To2-methoxy-6-methylbenzaldehyde (11.0 g, 73.25 mmol) in triethylamine(132 ml), hydroxylamine hydrochloride (6.10 g, 69.49 mmol) was added andheated to 80° C. After 3 h, the reaction mass was concentrated, quenchedwith water, extracted with ethyl acetate, dried over sodium sulphate andconcentrated to afford the title compound as off-white solid (7.50 g,62%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.54 (s, 1H), 8.31 (s, 1H), 7.24(t, J=7.9 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 3.85(s, 3H), 2.46 (s, 3H).

Intermediate 145: 2-methoxy-6-methylbenzonitrile: To intermediate 144(7.50 g, 45.41 mmol) in dichloromethane (55 ml), N,N′-dicarbonyldiimidazole (8.09 g, 49.95 mmol) was added and stirred at roomtemperature for 15 h. The reaction mass was quenched with water,extracted with dichloromethane, dried over sodium sulphate andconcentrated to afford the title compound as brown solid (5.0 g, 75%).¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.41 (t, J=8.1 Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 2.50 (s, 3H).

Intermediate 146: 1-(2-methoxy-6-methylphenyl)-2-phenylethanone: Tointermediate 145 (5.0 g, 34.03 mmol) in THF (50 ml), benzylmagnesiumchloride (34 ml, 2M in THF, 68.02 mmol) was added at 0° C. over 30 min.and heated to reflux for 15 h. The reaction mixture was cooled to roomtemperature, 2N HCl (200 ml) was added and again refluxed for 4 h. Thereaction mixture was cooled and extracted with ethyl acetate, dried oversodium sulphate and concentrated. The crude product was columnchromatographed with ethyl acetate:petroleum ether to afford to affordthe title compound as brown liquid (3.7 g, 45%). ¹H-NMR (δ ppm, CDCl₃,400 MHz): 7.30-7.18 (m, 6H), 6.76 (m, 2H), 4.07 (s, 2H), 3.83 (s, 3H),2.02 (s, 3H).

Intermediate 147: 1-(2-hydroxy-6-methylphenyl)-2-phenylethanone: Tointermediate 146 (2.0 g, 8.31 mmol) in dichloromethane (20 ml) at −78°C., boron tribromide (2.84 ml, 1M in dichloromethane, 16.64 mmol) wasadded slowly and maintained for 4 h. The reaction mass was quenched at−78° C. using 2N HCl (50 ml), extracted with ethyl acetate, dried oversodium sulphate and concentrated. The crude product was columnchromatographed with ethyl acetate:petroleum ether to afford to affordthe title compound as off-white solid (1.20 g, 64%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 11.18 (s, 1H), 7.37-7.27 (m, 4H), 7.19 (m, 2H), 6.84(d, J=8.3 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 4.27 (s, 2H), 2.62 (s, 3H).

Intermediate 148:2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one: Tointermediate 147 (0.400 g, 1.76 mmol) in dichloromethane (4 ml),R(+)-benzyloxypropionic acid (0.382 g, 2.12 mmol) and HATU (2.01 g, 5.30mmol) were added followed by triethylamine (2.6 ml, 19.08 mmol). After20 h at room temperature, the reaction mixture was quenched with water,extracted with ethyl acetate, dried over sodium sulphate andconcentrated. The crude product was column chromatographed with ethylacetate:petroleum ether to afford to afford the title compound asoff-white solid (0.080 g, 12%). ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 7.55 (t,J=8.1 Hz, 1H), 7.43-7.13 (m, 12H), 4.47 (m, 2H), 4.30 (d, J=11.8 Hz,1H), 2.84 (s, 3H), 21.54 (d, J=6.5 Hz, 3H).

Intermediate 149: 2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one:To intermediate 148 (0.140 g, 0.377 mmol) in dichloromethane (2.0 ml) at−78° C., boron tribromide (0.12 ml, 1M in dichloromethane, 0.755 mmol)was added slowly and maintained for 4 h. The reaction mass was quenchedat −78° C. using 2N HCl (50 ml), extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was columnchromatographed with ethyl acetate:petroleum ether to afford to affordthe title compound as pale-yellow liquid (0.100 g, 95%) which was usedas such in next step.

Intermediate 150: 3-bromo-5-fluoro-2-(1-hydroxyethyl)-4H-chromen-4-one:The title compound was obtained as a pale brown solid (1.90 g, 61%) byusing a procedure that is similar to the one described for intermediate23 from intermediate 28 (3.90 g, 11.14 mmol), DMSO (40 ml) and n-butanol(3.0 ml) which was used as such in next step.

Intermediate 151: 2-acetyl-3-bromo-5-fluoro-4H-chromen-4-one: The titlecompound was obtained as a pale yellow solid (0.80 g, 80%) by using aprocedure that is similar to the one described for intermediate 24 fromintermediate 150 (1.00 g, 3.48 mmol), DMSO (0.98 ml, 13.92 mmol),dichloromethane (104 ml), oxalyl chloride (0.59 ml, 6.96 mmol) andtriethylamine (2 ml). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.73 (dt, J=8.4,5.4 Hz, 1H), 7.36 (td, J=8.6, 0.9 Hz, 1H), 7.18 (m, 1H), 2.70 (s, 3H).

Intermediate 152: 2-acetyl-5-fluoro-3-o-tolyl-4H-chromen-4-one: Thetitle compound was obtained as a pale brown solid (0.165 g, 32%) byusing a procedure that is similar to the one described for intermediate21 from intermediate 151 (0.500 g, 1.75 mmol), 2-methylphenylboronicacid (0.382 g, 2.80 mmol), dioxane (11 ml), potassium acetate (0.573 g,3.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.140mmol) which was used as such in next step.

Intermediate 153:(R)/(S)-5-fluoro-2-(1-hydroxyethyl)-3-o-tolyl-4H-chromen-4-one: To asolution of intermediate 152 (0.155 g, 0.523 mmol) in DMF (2 ml) undernitrogen purging, formic acid:trietylamine 5:2 azeotrope (0.5 ml) wasadded followed by [(S,S)tethTsDpenRuCl] (1 mg). The reaction mixture washeated at 80° C. for 1.5 h under continuous nitrogen purging. Thereaction mixture was quenched with water, extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as a off-white solid (0.090 g, 66%) which wasused as such in next step.

EXAMPLES Example 1 2-(6-Amino-9H-purin-9-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one

2-(6-Amino-9H-purin-9-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one:To a solution of adenine (0.030 g, 0.222 mmol) in DMF (2 ml), potassiumcarbonate (0.061 g, 0.444 mmol) was added and stirred at RT for 10 min.To this mixture intermediate 10 (0.120 g, 0.333 mmol) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol:dichloromethane toafford the title compound as an off-white solid (0.028 g, 30%). ¹H-NMR(δ ppm, DMSO-D₆, 400 MHz): 8.09 (s, 1H), 8.07 (s, 1H), 7.64 (t, J=8.4Hz, 1H), 7.46 (dd, J=15.0, 6.7 Hz, 1H), 7.22-7.20 (m, 5H), 6.98 (d,J=8.3 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 5.26 (s, 2H), 3.81 (s, 3H).

Example 22-((4-Amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one

2-((4-Amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one:To a solution of Intermediate 13 (0.060 g, 0.220 mmol) in DMF (2 ml),potassium carbonate (0.060 g, 0.440 mmol) was added and stirred at RTfor 10 min. To this mixture intermediate 9 (0.120 g, 0.330 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography withmethanol:dichloromethane to afford the title compound as a pale yellowsolid (0.035 g, 28%). MP: 145-148° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):8.37 (s, 1H), 7.51 (t, J=8.3 Hz, 1H), 7.42-7.29 (m, 3H), 7.18-7.09 (m,3H), 7.00 (t, J=6.8 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.3 Hz,1H), 5.53 (s, 2H), 5.47 (s, 2H), 4.66 (quintet, J=6.0 Hz, 1H), 3.98 (s,3H), 1.41 (d, J=5.9 Hz, 6H).

Example 32-((4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-((4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of Intermediate 13 (0.100 g, 0.367 mmol) in DMF (2 ml),potassium carbonate (0.101 g, 0.734 mmol) was added and stirred at RTfor 10 min. To this mixture intermediate 17 (0.173 g, 0.550 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography withmethanol:dichloromethane to afford the title compound as a pale brownsolid (0.011 g, 5%). MP: 156-159° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):8.20 (s, 1H), 8.79 (dd, J=13.9, 8.2 Hz, 1H), 7.63-7.53 (m, 4H),7.40-7.22 (m, 5H), 7.15 (m, 2H), 5.47 (s, 2H), 4.71 (quintet, J=5.9 Hz,1H), 1.32 (d, J=5.9 Hz, 6H).

Example 42-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150g, 0.578 mmol) in DMF (2 ml), potassium carbonate (0.159 g, 1.15 mmol)was added and stirred at RT for 10 min. To this mixture intermediate 17(0.564 g, 1.78 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as a pale brown solid (0.200 g, 65%) which is used as such fornext step.

Example 52-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution example 4 (0.200 g, 0.377 mmol) in dichloromethane (2 ml)at 0° C., boron tribromide (1M in dichloromethane, 2 ml) was added andwarmed to RT and stirred for 12 h. The reaction mixture was quenched bythe addition of aq.HCl solution and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as a pale brown solid(0.030 g, 15%). MP: 136-138° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): 10.17(s, 1H), 8.22 (s, 1H), 7.78 (dt, J=14.2, 8.3 Hz, 1H), 7.63 (dd, J=12.0,7.3 Hz, 1H), 7.56 (m, 1H), 7.38-7.23 (m, 3H), 7.14-7.07 (m, 3H), 6.85(s, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.65 (d, J=10.8 Hz, 1H), 5.50 (s, 2H).

Example 62-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of 13 (0.120 g, 0.440 mmol) in DMF (2 ml), potassiumcarbonate (0.121 g, 0.881 mmol) was added and stirred at RT for 10 min.To this mixture intermediate 22 (0.217 g, 0.661 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol:dichloromethane toafford the title compound as a off-white solid (0.120 g, 48%). MP:228-230° C. ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 8.23 (s, 1H), 7.62 (dt,J=8.4, 5.9 Hz, 1H), 7.44 (d, J=11.5, 1.8 Hz, 1H), 7.37 (d, J=8.4 Hz,1H), 7.31 (m, 2H), 7.14 (t, J=8.4 Hz, 1H), 7.06 (m, 3H), 6.92 (d, J=9.5Hz, 1H), 6.07 (q, J=7.1 Hz, 1H), 5.52 (s, 2H), 4.65 (quintet, J=6.1 Hz,1H), 1.99 (d, J=7.1 Hz, 3H), 1.42 (d, J=6.1 Hz, 6H).

Example 7 and 8(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-oneand(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

The two enantiomerically pure isomers were separated by preparative SFCconditions from example 6 (0.300 g) on a CHIRALPAK AS-H column (250×4.6mm; 5 m) using methanol: CO₂ (30:70) as the mobile phase at a flow rateof 3.0 ml/min.

Example 7: Off-white solid (0.145 g). e.e. 98.16%. Rt: 2.06 min. [ ]²⁵_(D) 177.47 (c=1, CHCl₃). MP: 217-220° C. Mass: 571.2 (M+).

Example 8: Off-white solid (0.136 g). e.e. 100%. Rt: 2.73 min. [α]²⁵_(D) −173.56 (c=1, CHCl₃). MP: 218-221° C. Mass: 571.8 (M⁺).

Example 92-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 27 (0.100 g, 0.183 mmol) in1,2-dimethoxyethane (2 ml), and water (1 ml),3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.099 g, 0.275 mmol) and sodium carbonate (0.058 g, 0.549 mmol) wereadded and the system is degassed for 30 min.Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.030 g,0.036 mmol) was added under nitrogen atmosphere and degassed for 30 minand kept under microwave irradiation (microwave power=100 W,temperature=100° C.) for 1 h. The reaction mixture was filtered throughcelite, washed with ethyl acetate, dried over sodium sulphate andconcentrated. The residue was dissolved in dichloromethane (2 ml) andtriflutoacetic acid (2 ml) was added and stirred for 1 h. The reactionmixture neutralised with aq.sodium bicarbonate solution, extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as brown solid (0.033 g, 33% yield). MP: 156-159° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.21 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.73 (s,1H), 7.60 (dt, J=8.4, 5.5 Hz, 1H), 7.45 (dd, J=8.2, 1.1 Hz, 1H), 7.29(m, 2H), 7.06-6.98 (m, 4H), 6.10 (q, J=7.2 Hz, 1H), 5.89 (m, 1H), 2.64(s, 3H), 1.96 (d, J=7.2 Hz, 3H).

Example 9a and 9b(+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-oneand(−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

The two enantiomerically pure isomers were separated by preparative SFCconditions from example 9 (0.300 g) on a CHIRALPAK AD-H column (250×4.6mm; 5 m) using methanol: CO₂ (30:70) as the mobile phase at a flow rateof 3.0 ml/min.

Example 9a: Brown solid (0.097 g). e.e. 98.12%. Rt: 4.54 min. [α]²⁵ _(D)161.30 (c=1, CHCl₃). MP: 190-192° C. Mass: 549.8 (M+).

Example 9b: Brown solid (0.098 g). e.e. 96.1%. Rt: 5.92 min. [α]²⁵ _(D)−209.90 (c=1, CHCl₃). MP: 193-195° C. Mass: 549.2 (M⁺).

Example 102-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.016 g, 18%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml),water (1 ml), 1-Boc-pyrazole-4-boronic acid (0.058 g, 0.275 mmol),sodium carbonate (0.058 g, 0.549 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.030 g,0.036 mmol) MP: 165-168° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.24 (s,1H), 7.94 (s, 2H), 7.59 (m, 1H), 7.28 (m, 2H), 7.04-6.87 (m, 4H), 6.04(q, J=7.0 Hz, 1H), 5.49 (s, 2H), 1.99 (d, J=7.1 Hz, 3H).

Example 112-(1-(6-amino-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale green solid (0.047 g, 26%) byusing a procedure that is similar to the one described for example 6from adenine (0.116 g, 0.864 mmol), DMF (5 ml), potassium carbonate(0.140 g, 1.08 mmol) and intermediate 22 (0.150 g, 0.432 mmol) MP:222-224° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.44 (s, 1H), 8.03 (s,1H), 7.82 (dt, J=8.4, 5.7 Hz, 1H), 7.51 (m, 2H), 7.27-7.16 (m, 6H), 5.64(q, J=7.0 Hz, 1H), 1.88 (d, J=7.2 Hz, 3H).

Example 122-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

22-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.085 g, 38%) byusing a procedure that is similar to the one described for example 6from intermediate 13 (0.150 g, 0.522 mmol), DMF (2 ml), potassiumcarbonate (0.152 g, 1.10 mmol) and intermediate 31 (0.272 g, 0.0.744mmol) MP: 218-221° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.24 (s, 1H), 7.61(dt, J=8.5, 5.5 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.35 (d, J=9.0Hz, 1H), 7.23 (m, 3H), 7.15 (t, J=8.4 Hz, 1H), 7.08 (m, 3H), 6.06 (q,J=7.1 Hz, 1H), 5.79 (s, 2H), 4.67 (quintet, J=6.1 Hz, 1H), 1.99 (d,J=7.1 Hz, 3H), 1.42 (d, J=7.1 Hz, 6H).

Example 132-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as off-white solid (0.060 g, 25%) byusing a procedure that is similar to the one described for example 6from intermediate 13 (0.150 g, 0.522 mmol), DMF (2 ml), potassiumcarbonate (0.152 g, 1.10 mmol) and intermediate 33 (0.291 g, 0.838 mmol)MP: 226-229° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.22 (s, 1H), 7.60 (dt,J=8.5, 5.5 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.36 (m, 4H), 7.23(m, 3H), 7.14 (t, J=8.4 Hz, 1H), 7.04 (t, J=9.7 Hz, 1H), 6.06 (q, J=7.2Hz, 1H), 5.52 (s, 2H), 4.64 (quintet, J=6.1 Hz, 1H), 1.98 (d, J=7.1 Hz,3H), 1.42 (d, J=6.0 Hz, 6H).

Example 142-(1-(4-amino-3-(benzofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(benzofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.026 g, 26%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml),water (1 ml), benzofuran-2-boronic acid (0.045 g, 0.275 mmol), sodiumcarbonate (0.058 g, 0.549 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.062 g,0.073 mmol) MP: 238-241° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.27 (s,1H), 7.70 (d, J=8.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.41 (s, 1H), 7.39 (m,3H), 7.28 (m, 1H), 7.07-6.99 (m, 4H), 6.07 (q, J=8.1 Hz, 1H), 2.05 (d,J=8.3 Hz, 3H).

Example 152-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 36 (0.20 g, 0.663 mmol), tert-butanol (1.5ml) N,N-diisopropylethylamine (0.23 ml, 1.32 mmol) and 6-chloropurine(0.102 g, 0.663 mmol) were added and heated to reflux for 48 h. Thereaction mixture was concentrated, quenched with water, extracted withethyl acetate, dried with sodium sulphate and concentrated. The crudeproduct was purified by column chromatography with methanol:ethylacetate to afford the title compound as brown solid (0.080 g, 30%yield). MP: 195-198° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.96 (s, 1H),8.17 (s, 1H), 8.09 (s, 1H), 7.21-6.94 (m, 5H), 6.71 (m, 2H), 5.64 (m,1H), 1.52 (br s, 3H).

Example 162-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

22-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.030 g, 25%) by using aprocedure that is similar to the one described for example 6 from1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.077 g, 0.576 mmol), DMF (1 ml),potassium carbonate (0.099 g, 0.720 mmol) and intermediate 22 (0.100 g,0.288 mmol). MP: 267-269° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.25 (s,1H), 7.92 (s, 1H), 7.61 (dt, J=8.4, 5.4 Hz, 1H), 7.32 (m, 2H), 7.06 (m,3H), 6.92 (d, J=9.7 Hz, 1H), 6.02 (q, J=7.1 Hz, 1H), 5.41 (s, 2H), 1.96(d, J=7.1 Hz, 3H).

Example 16a and 16b(+)-22-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-oneand(−)-2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

The two enantiomerically pure isomers were separated by preparative SFCconditions from example 16 (0.300 g) on a CHIRALPAK AD-H column (250×4.6mm; 5 m) using methanol: CO₂ (30:70) as the mobile phase at a flow rateof 3.0 ml/min.

Example 16a: Off-white solid (0.145 g). e.e. 98.07%. Rt: 2.49 min. [α]²⁵_(D) 90.52 (c=1, CHCl₃). MP: 197-200° C. Mass: 419.8 (M⁺).

Example 16b: Off-white solid (0.150 g). e.e. 98.8%. Rt: 3.56 min. [α]²⁵_(D) −73.03 (c=1, CHCl₃). MP: 198-201° C. Mass: 419.8 (M⁺).

Example 172-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.042 g, 27%) byusing a procedure that is similar to the one described for example 6from intermediate 39 (0.081 g, 0.273 mmol), DMF (2 ml), potassiumcarbonate (0.075 g, 0.546 mmol) and intermediate 22 (0.100 g, 0.0.273mmol) MP: 230-233° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.26 (s, 1H), 7.62(dt, J=8.4, 5.4 Hz, 1H), 7.56 (dd, J=10.3, 1.3 Hz, 1H), 7.47 (m, 2H),7.32 (d, J=6.5 Hz, 1H), 7.27 (m, 1H), 7.06 (m, 3H), 6.91 (d, J=9.1 Hz,1H), 6.81 (t, J=72.9 Hz, 1H), 6.63 (s, 2H), 6.07 (q, J=7.2 Hz, 1H), 1.99(d, J=7.1 Hz, 3H).

Example 182-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.020 g, 20%) by using aprocedure that is similar to the one described for example 9 fromintermediate 29 (0.100 g, 0.188 mmol), 1,2-dimethoxyethane (2 ml), water(1 ml), 1-Boc-pyrazole-4-boronic acid (0.098 g, 0.282 mmol), sodiumcarbonate (0.059 g, 0.565 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.030 g,0.037 mmol) MP: 181-184° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.34 (s,1H), 7.93 (s, 2H), 7.57 (dt, J=8.4, 5.5 Hz, 1H), 7.47 (dd, J=11.5, 2.0Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.24 (m, 1H), 7.15 (t, J=8.4 Hz, 1H),7.04 (dd, J=10.2, 8.9 Hz, 1H), 6.36 (q, J=7.1 Hz, 1H), 5.51 (s, 2H),4.65 (q, J=6.0 Hz, 1H), 2.03 (d, J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H).

Example 192-(1-(4-amino-3-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: Thetitle compound was obtained as brown solid (0.022 g, 22%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water(1 ml), intermediate 41 (0.070 g, 0.276 mmol), sodium carbonate (0.038g, 0.366 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.030 g, 0.036 mmol). MP: 234-237° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.24 (s, 1H), 7.62 (dt, J=8.4, 5.5 Hz, 1H), 7.46(dd, J=11.4, 1.9 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.32 (m, 2H), 7.17 (t,J=8.3 Hz, 1H), 7.06-6.96 (m, 3H), 6.90 (d, J=8.8 Hz, 1H), 6.08 (q, J=7.0Hz, 1H), 5.44 (s, 2H), 4.58 (quintet, J=3.9 Hz, 1H), 4.05 (m, 2H), 3.62(m, 2H), 2.09 (m, 2H), 1.99 (d, J=7.1 Hz, 3H), 1.91 (m, 2H).

Example 202-(1-(4-amino-3-(3-isopropyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-isopropyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.026 g, 13%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water(1 ml), intermediate 46 (0.140 g, 0.276 mmol), sodium carbonate (0.038g, 0.366 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.030 g, 0.036 mmol). MP: 249-252° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.25 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.74 (s,1H), 7.61 (dt, J=8.4, 5.4 Hz, 1H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 7.30(m, 2H), 7.06-6.95 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.10 (q, J=7.1 Hz,1H), 5.47 (s, 2H), 3.48 (q, J=7.1 Hz, 1H), 2.02 (d, J=7.1 Hz, 3H), 1.50(d, J=7.1 Hz, 6H).

Example 212-(1-(4-amino-3-(3-fluoro-4-(piperidin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(piperidin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.030 g, 13%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml), water(1 ml), intermediate 48 (0.150 g, 0.276 mmol), sodium carbonate (0.038g, 0.366 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.030 g, 0.036 mmol). MP: 280-283° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.06 (s, 1H), 7.83 (dt, J=8.4, 5.7 Hz, 1H), 7.49(d, J=8.5 Hz, 1H), 7.41 (dd, J=12.6, 1.5 Hz, 1H), 7.34 (m, 4H), 7.07(dt, J=8.9, 2.6 Hz, 1H), 6.92 (m, 2H), 5.96 (q, J=7.0 Hz, 1H), 4.50 (m,1H), 3.40 (m, 1H), 2.99 (m, 2H), 2.62 (m, 2H), 1.97 (m, 2H), 1.87 (d,J=7.0 Hz, 3H), 1.54 (m, 2H).

Example 222-(1-(4-amino-3-(3-fluoro-4-(2-hydroxyethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(2-hydroxyethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.018 g, 9%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 52 (0.167 g, 0.411 mmol), sodium carbonate (0.058g, 0.549 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.045 g, 0.054 mmol). MP: 154-157° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.20 (s, 1H), 7.61 (dt, J=8.4, 5.4 Hz, 1H),7.34-7.28 (m, 4H), 7.06-6.96 (m, 3H), 6.91 (d, J=9.0 Hz, 1H), 6.87 (t,J=8.3 Hz, 1H), 6.06 (q, J=7.1 Hz, 1H), 5.62 (s, 2H), 4.51 (s, 1H), 3.92(t, J=5.1 Hz, 2H), 3.42 (t, J=5.2 Hz, 2H), 2.09 (s, 1H), 1.98 (d, J=7.1Hz, 3H).

Example 232-(1-(4-amino-3-(3-fluoro-4-(isopropylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(isopropylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.065 g, 25%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml), water(1 ml), intermediate 56 (0.192 g, 0.686 mmol), sodium carbonate (0.097g, 0.915 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.074 g, 0.091 mmol). MP: 224-226° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.04 (s, 1H), 7.83 (dt, J=8.4, 5.6 Hz, 1H), 7.49(d, J=8.6 Hz, 1H), 7.28-7.21 (m, 4H), 7.06 (dt, J=8.4, 1.8 Hz, 1H),6.91-6.82 (m, 3H), 5.95 (q, J=6.7 Hz, 1H), 5.37 (d, J=6.6 Hz, 1H), 3.72(m, 1H), 1.86 (d, J=7.0 Hz, 3H), 1.19 (d, J=6.2 Hz, 6H).

Example 242-(1-(4-amino-3-(4-(dimethylamino)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(dimethylamino)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.070 g, 28%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml),water (1 ml), intermediate 60 (0.182 g, 0.686 mmol), sodium carbonate(0.097 g, 0.915 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.074 g, 0.091 mmol). MP: 252-254° C. ¹H-NMR NMR(δ ppm, DMSO-d₆, 400 MHz): 8.06 (s, 1H), 7.83 (dt, J=8.5, 5.7 Hz, 1H),7.49 (d, J=8.7 Hz, 1H), 7.32-7.24 (m, 4H), 7.09 (m, 2H), 6.88 (m, 2H),5.95 (q, J=7.0 Hz, 1H), 2.85 (s, 6H), 1.87 (d, J=7.0 Hz, 3H).

Example 252-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.055 g, 33%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3 ml),water (1.5 ml), intermediate 61 (0.127 g, 0.411 mmol), sodium carbonate(0.058 g, 0.549 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.045 g, 0.054 mmol). MP: 270-272° C. ¹H-NMR NMR(δ ppm, CDCl₃, 400 MHz): 8.24 (s, 1H), 7.59 (dt, J=8.4, 5.4 Hz, 1H),7.40 (m, 2H), 7.27 (m, 2H), 7.09-6.86 (m, 5H), 6.06 (q, J=7.1 Hz, 1H),5.43 (s, 2H), 3.91 (t, J=4.6 Hz, 4H), 3.48 (t, J=4.7 Hz, 4H), 1.99 (d,J=7.1 Hz, 3H).

Example 262-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.032 g, 13%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.250 g, 0.457 mmol), 1,2-dimethoxyethane (4 ml),water (1 ml), tert-butyl2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate(0.246 g, 0.686 mmol), sodium carbonate (0.097 g, 0.915 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.074 g,0.091 mmol). MP: 236-238° C. ¹H-NMR NMR (δ ppm, CDCl₃, 400 MHz): 8.25(s, 1H), 7.81 (br s, 1H), 7.66 (m, 1H), 7.62 (dt, J=8.4, 5.4 Hz, 1H),7.52 (dd, J=8.2, 1.6 Hz, 1H), 7.30 (m, 2H), 7.06-6.95 (m, 3H), 6.92 (d,J=9.3 Hz, 1H), 6.10 (q, J=6.9 Hz, 1H), 5.71 (s, 2H), 2.67 (s, 3H), 2.01(d, J=7.2 Hz, 3H).

Example 272-(1-(4-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.080 g, 20%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.300 g, 0.549 mmol), 1,2-dimethoxyethane (5 ml),water (2.5 ml), intermediate 63 (0.260 g, 0.604 mmol), sodium carbonate(0.116 g, 1.09 mmol) and tetrakistriphenylphosphine palladium(0) (0.032g, 0.027 mmol). MP: 246-249° C. ¹H-NMR NMR (δ ppm, CDCl₃, 400 MHz): 8.23(s, 1H), 7.61 (dt, J=8.4, 5.4 Hz, 1H), 7.38 (m, 2H), 7.29 (m, 2H),7.08-6.96 (m, 4H), 6.91 (d, J=9.2 Hz, 1H), 6.07 (q, J=7.2 Hz, 1H), 5.51(s, 2H), 3.22 (t, J=4.6 Hz, 4H), 2.67 (t, J=4.6 Hz, 4H), 2.37 (s, 3H),1.98 (d, J=7.2 Hz, 3H).

Example 282-(1-(4-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.040 g, 18%) byusing a procedure that is similar to the one described for example 6from N,N-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.49mmol for preparation see J. Amer. Chem. Soc. 1956, 784-790), DMF (10ml), cesium carbonate (0.319 g, 0.546 mmol) and intermediate 22 (0.179g, 0.0.490 mmol) MP: 200-202° C. ¹H-NMR NMR (δ ppm, CDCl₃, 400 MHz):8.20 (s, 1H), 7.95 (s, 1H), 7.60 (dt, J=8.4, 5.5 Hz, 1H), 7.31 (m, 2H),7.05 (m, 3H), 6.86 (d, J=9.2 Hz, 1H), 6.02 (q, J=7.1 Hz, 1H), 3.36 (s,6H), 1.93 (d, J=7.1 Hz, 3H).

Example 292-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as pale green solid (0.030 g, 25%) byusing a procedure that is similar to the one described for example 6from 1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.061 g, 0.455 mmol), DMF (1ml), cesium carbonate (0.148 g, 0.455 mmol) and intermediate 33 (0.100g, 0.0.303 mmol). MP: 223-226° C. ¹H-NMR NMR (δ ppm, CDCl₃, 400 MHz):8.23 (s, 1H), 7.92 (s, 1H), 7.57 (dt, J=8.4, 5.4 Hz, 1H), 7.34 (m, 3H),7.23 (s, 1H), 7.19 (m, 2H), 7.04 (dt, J=8.2, 0.9 Hz, 1H), 6.01 (q, J=7.1Hz, 1H), 5.40 (s, 2H), 1.95 (d, J=7.1 Hz, 3H).

Example 302-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale green solid (0.040 g, 34%) byusing a procedure that is similar to the one described for example 6from 1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.058 g, 0.432 mmol), DMF (1ml), cesium carbonate (0.140 g, 0.432 mmol) and intermediate 31 (0.100g, 0.0.288 mmol). MP: 242-245° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.26(s, 1H), 7.92 (s, 1H), 7.60 (dt, J=8.4, 5.4 Hz, 1H), 7.25 (m, 3H),7.07-7.00 (m, 3H), 6.01 (q, J=7.2 Hz, 1H), 5.45 (s, 2H), 1.96 (d, J=7.1Hz, 3H).

Example 312-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.053 g, 33%) byusing a procedure that is similar to the one described for example 6from intermediate 39 (0.081 g, 0.273 mmol), DMF (2 ml), potassiumcarbonate (0.075 g, 0.546 mmol) and intermediate 31 (0.100 g, 0.0.273mmol) MP: 233-235° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.28 (s, 1H),7.61-7.55 (m, 2H), 7.47 (m, 2H), 7.25 (m, 3H), 7.08 (m, 3H), 6.82 (t,J=72.9 Hz, 1H), 6.01 (q, J=7.1 Hz, 1H), 5.42 (s, 2H), 1.99 (d, J=7.2 Hz,3H).

Example 322-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as off-white solid (0.021 g, 33%) byusing a procedure that is similar to the one described for example 6from intermediate 39 (0.090 g, 0.303 mmol), DMF (2 ml), potassiumcarbonate (0.084 g, 0.607 mmol) and intermediate 33 (0.100 g, 0.0.303mmol) MP: 247-250° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.22 (s, 1H),7.69-7.20 (m, 10H), 7.05 (dd, J=9.5, 8.5 Hz, 1H), 6.81 (t, J=72.9 Hz,1H), 6.08 (q, J=7.1 Hz, 1H), 5.43 (s, 2H), 1.99 (d, J=7.1 Hz, 3H).

Example 332-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.025 g, 21%) byusing a procedure that is similar to the one described for example 6from 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.043 g, 0.288 mmolfor preparation see J. Org. Chem. 1956, 21, 1240-1256), DMF (2 ml),potassium carbonate (0.079 g, 0.576 mmol) and intermediate 22 (0.100 g,0.0.288 mmol). MP: 240-242° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.16(s, 1H), 7.59 (dt, J=8.4, 3.4 Hz, 1H), 7.29 (m, 2H), 7.06-6.84 (m, 4H),5.94 (q, J=7.1 Hz, 1H), 5.42 (s, 2H), 2.59 (s, 3H), 1.92 (d, J=7.1 Hz,3H).

Example 342-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.038 g, 30%) byusing a procedure that is similar to the one described for example 6from intermediate 66 (0.048 g, 0.288 mmol), DMF (2 ml), potassiumcarbonate (0.079 g, 0.576 mmol) and intermediate 22 (0.100 g, 0.0.288mmol) MP: 196-198° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.18 (s, 1H), 7.60(dt, J=8.4, 3.0 Hz, 1H), 7.29 (m, 2H), 7.05-6.78 (m, 4H), 5.94 (q, J=7.2Hz, 1H), 5.31 (s, 2H), 2.95 (q, J=6.6 Hz, 2H), 1.93 (d, J=7.2 Hz, 3H),1.40 (d, J=76 Hz, 3H).

Example 352-(1-(4-amino-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: The title compound was obtained as off-whitesolid (0.035 g, 18%) by using a procedure that is similar to the onedescribed for example 6 from3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.079 g, 0.432 mmol forpreparation see J. Amer. Chem. Soc. 2002, 124, 12118), DMF (3 ml),potassium carbonate (0.119 g, 0.864 mmol) and intermediate 22 (0.150 g,0.0.432 mmol) MP: 212-214° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.19 (s,1H), 7.59 (dt, J=8.5, 5.4 Hz, 1H), 7.32 (m, 2H), 7.03-6.92 (m, 4H), 5.93(q, J=7.5 Hz, 1H), 5.34 (s, 2H), 3.20 (m, 1H), 1.93 (d, J=7.2 Hz, 3H),1.43 (d, J=6.9 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H).

Example 362-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.070 g, 15%) by using aprocedure that is similar to the one described for example 6 fromintermediate 67 (0.294 g, 1.10 mmol), DMF (3 ml), cesium carbonate(0.358 g, 1.10 mmol) and intermediate 22 (0.300 g, 0.0.864 mmol). MP:248-250° C. ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 8.28 (s, 1H), 7.91 (m, 2H),7.62 (s, 1H), 7.60 (dt, J=8.0, 3.0 Hz, 1H), 7.44 (m, 2H), 7.29 (m, 2H),7.06 (m, 4H), 6.08 (q, J=7.1 Hz, 1H), 5.73 (s, 2H), 2.02 (d, J=7.1 Hz,3H).

Example 372-(1-(4-amino-3-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as yellow solid (0.040 g, 18%) by usinga procedure that is similar to the one described for example 6 fromintermediate 70 (0.114 g, 0.518 mmol), DMF (2 ml), potassium carbonate(0.119 g, 0.864 mmol) and intermediate 22 (0.150 g, 0.0.432 mmol). MP:171-173° C. ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 8.15 (s, 1H), 7.62 (dt,J=8.4, 5.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.06-6.99 (m, 3H), 6.90 (d, J=9.4Hz, 1H), 5.89 (d, J=7.2 Hz, 1H), 5.29 (s, 2H), 3.88 (t, J=4.6 Hz, 4H),3.32 (t, J=4.6 Hz, 4H), 1.91 (d, J=7.2 Hz, 3H).

Example 382-(1-(4-amino-3-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.032 g, 14%) by using aprocedure that is similar to the one described for example 6 fromintermediate 73 (0.092 g, 0.518 mmol), DMF (2 ml), cesium carbonate(0.119 g, 0.432 mmol) and intermediate 22 (0.150 g, 0.0.432 mmol). MP:169-171° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.14 (s, 1H), 7.61 (dt,J=8.4, 5.4 Hz, 1H), 7.29 (m, 2H), 7.05 (m, 3H), 6.89 (d, J=8.9 Hz, 1H),5.87 (q, J=7.0 Hz, 1H), 5.46 (s, 2H), 2.86 (s, 6H), 1.01 (d, J=7.1 Hz,3H).

Example 392-(1-(4-amino-3-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.014 g, 10%) by using aprocedure that is similar to the one described for example 6 fromintermediate 76 (0.063 g, 0.288 mmol), DMF (1 ml), cesium hydroxide(0.048 g, 0.288 mmol) and intermediate 22 (0.100 g, 0.0.288 mmol). MP:160-162° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.14 (s, 1H), 7.55 (dt,J=8.4, 5.5 Hz, 1H), 7.29 (m, 2H), 7.05 (m, 3H), 6.89 (d, J=8.9 Hz, 1H),5.85 (q, J=7.1 Hz, 1H), 5.41 (s, 2H), 3.48 (t, J=7.1 Hz, 4H), 1.90 (d,J=7.1 Hz, 3H), 1.73-1.61 (m, 6H).

Example 402-(1-(4-amino-3-(6-isopropoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(6-isopropoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.028 g, 28%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.100 g, 0.183 mmol), 1,2-dimethoxyethane (2 ml),water (1 ml),2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.072 g, 0.274 mmol), sodium carbonate (0.038 g, 0.366 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.029 g, 0.036 mmol). MP: 196-199° C. ¹H-NMR NMR (δ ppm, CDCl₃, 400MHz): 8.45 (d, J=2.3 Hz, 1H), 8.25 (s, 1H), 7.87 (dd, J=8.6, 2.5 Hz,1H), 7.62 (dt, J=8.4, 5.5 Hz, 1H), 7.32 (m, 2H), 7.06 (m, 3H), 6.92 (d,J=9.2 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.06 (q, J=7.1 Hz, 1H), 5.40(quintet, J=6.3 Hz, 1H), 5.37 (s, 2H), 1.99 (d, J=7.1 Hz, 3H), 1.40 (d,J=6.2 Hz, 6H).

Example 412-(1-(4-amino-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.030 g, 22%) by using aprocedure that is similar to the one described for example 6 from3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.078 g, 0.432 mmolfor preparation see J. Het. Chem. 1990, 27, 775-783), DMF (2 ml), cesiumcarbonate (0.140 g, 0.432 mmol) and intermediate 22 (0.100 g, 0.228mmol). MP: 102-105° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.19 (s, 1H),7.61 (dt, J=8.4, 5.4 Hz, 1H), 7.34 (m, 2H), 7.06 (m, 3H), 6.95 (d, J=9.5Hz, 1H), 5.95 (q, J=7.1 Hz, 1H), 5.82 (s, 2H), 2.63 (s, 6H), 1.95 (d,J=7.1 Hz, 3H).

Example 422-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate: To example 6 (0.100 g, 0.174 mmol) inisopropanol (4 ml), p-toluenesulphonic acid (0.037 g, 0.192 mmol) wasadded and refluxed for 1 h. The reaction mixture was concentrated,co-distilled with pet. ether and dried. To the residue water (3 ml) wasadded and stirred for 30 min. The solid was filtered, washed with pet.ether and dried under vacuum to afford the title compound as off-whitesolid (0.102 g, 78%). MP: 153-156° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.15 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.64 (dt, J=8.4, 5.4 Hz, 1H), 7.42(dd, J=11.2, 2.0 Hz, 1H), 7.34 (m, 3H), 7.22 (d, J=8.0 Hz, 2H), 7.15 (t,J=8.4 Hz, 1H), 7.08-6.99 (m, 3H), 6.87 (m, 1H), 6.07 (q, J=7.1 Hz, 1H),4.67 (quintet, J=6.1 Hz, 1H), 2.37 (s, 3H), 2.01 (d, J=7.2 Hz, 3H), 1.43(d, J=6.1 Hz, 6H).

Example 432-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate

2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate: The title compound was obtained as off-whitesolid (0.120 g, 84%) by using a procedure that is similar to the onedescribed for example 43 from example 9 (0.10 g, 0.200 mmol),isopropanol (4 ml) and p-toluenesulphonic acid (0.042 g, 0.220 mmol).MP: 172-175° C. 6 ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 10.15 (s, 1H), 8.08(s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J=8.1 Hz, 2H),7.61 (dt, J=8.2, 3.0 Hz, 1H), 7.38 (m, 3H), 7.27 (m, 1H), 7.11-6.88 (m,7H), 6.08 (q, J=6.9 Hz, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 2.04 (d, J=7.2Hz, 3H).

Example 442-(1-(4-amino-3-(4-(1-benzhydrylazetidin-3-yloxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(1-benzhydrylazetidin-3-yloxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.035 g, 13%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml),water (1.5 ml), intermediate 81 (0.252 g, 0.550 mmol), sodium carbonate(0.116 g, 1.10 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.060 g, 0.073 mmol). MP: 211-214° C. 6 ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.23 (s, 1H), 7.59 (dt, J=8.4, 5.4 Hz, 1H), 7.44(m, 5H), 7.29-7.18 (m, 9H), 7.05 (m, 3H), 6.90 (m, 1H), 6.86 (t, J=8.4Hz, 1H), 6.04 (q, J=7.2 Hz, 1H), 5.35 (s, 2H), 4.91 (quintet, J=4.7 Hz,1H), 4.47 (s, 1H), 3.78 (m, 2H), 3.23 (m, 2H), 1.97 (d, J=7.2 Hz, 3H).

Example 452-(1-(4-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.043 g, 19%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml),water (1.5 ml), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (0.122g, 0.550 mmol for preparation see J. Med. Chem. 2010, 53, 8421-8439),sodium carbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 247-249° C. Mass: 598.0 (M⁺)

Example 462-(1-(4-amino-3-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.040 g, 18%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml),water (1.5 ml), intermediate 83 (0.162 g, 0.550 mmol), sodium carbonate(0.116 g, 1.10 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.060 g, 0.073 mmol). MP: 235-237° C. Mass:586.2.0 (M⁺+1).

Example 472-(1-(4-amino-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as yellow solid (0.040 g, 10%) by usinga procedure that is similar to the one described for example 6 fromintermediate 79 (0.211 g, 1.03 mmol), DMF (4 ml), cesium carbonate(0.281 g, 0.864 mmol) and intermediate 22 (0.300 g, 0.0.864 mmol). MP:203-205° C. Mass: 489.1 (M⁺+1).

Example 48N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide:The title compound was obtained as pale brown solid (0.047 g, 22%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml),water (1.0 ml), 4-isobutyramidophenylboronic acid (0.114 g, 0.550 mmol),sodium carbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 154-157° C. Mass: 581.1 (M⁺+1).

Example 492-(1-(4-amino-3-(4-isobutylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-isobutylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.061 g, 30%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water(1.0 ml), 4-isobutylphenylboronic acid (0.098 g, 0.550 mmol), sodiumcarbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 221-223° C. Mass: 552.3 (M⁺+1).

Example 502-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale brown solid (0.038 g, 31%) byusing a procedure that is similar to the one described for example 6from intermediate 84 (0.060 g, 0.211 mmol), DMF (2 ml), sodium carbonate(0.059 g, 0.423 mmol) and intermediate 22 (0.116 g, 0.317 mmol). MP:185-188° C. Mass: 568.0 (M⁺+1).

Example 512-(1-(4-amino-3-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.035 g, 17%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water(1.0 ml), 4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenylboronic acid (0.113 g,0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 228-230° C. Mass: 579.1 (M⁺+1).

Example 524-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzenesulfonamide

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzenesulfonamide:The title compound was obtained as brown solid (0.060 g, 28%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.5 ml),water (1.5 ml), 4-(N-methylsulfamoyl)phenylboronic acid (0.118 g, 0.550mmol), sodium carbonate (0.077 g, 0.732 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 175-178° C. Mass: 589.1 (M⁺+1).

Example 534-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-N-isopropylbenzamide

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-N-isopropylbenzamide:The title compound was obtained as brown solid (0.063 g, 29%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.5 ml),water (1.5 ml), 3-fluoro-4-(isopropylcarbamoyl)phenylboronic acid (0.123g, 0.550 mmol), sodium carbonate (0.077 g, 0.732 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 254-257° C. Mass: 599.1 (M⁺+1).

Example 542-(1-(4-amino-3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.068 g, 41%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0ml), water (1.5 ml),4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenylboronic acid (0.097 g,0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 199-201° C. Mass: 609.0 (M⁺).

Example 55N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methanesulfonamide

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methanesulfonamide:The title compound was obtained as brown solid (0.055 g, 33%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-(methylsulfonamidomethyl)phenylboronic acid (0.094 g,0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 252-255° C. Mass: 603.0 (M⁺+1).

Example 564-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzenesulfonamide

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzenesulfonamide:The title compound was obtained as off-white solid (0.075 g, 44%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0ml), water (1.5 ml), 4-(N-isopropylsulfamoyl)phenylboronic acid (0.100g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 211-214° C. Mass: 616.9 (M⁺).

Example 574-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzenesulfonamide

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzenesulfonamide:The title compound was obtained as brown solid (0.043 g, 26%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-(N-cyclopropylsulfamoyl)phenylboronic acid (0.099 g,0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 225-228° C. Mass: 614.8 (M⁺).

Example 582-(1-(4-amino-3-(2-isopropoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(2-isopropoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.025 g, 12%) byusing a procedure that is similar to the one described for example 9from intermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.0ml), water (1.5 ml), intermediate 85 (0.146 g, 0.550 mmol), sodiumcarbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 230-232° C. Mass: 556.0 (M⁺+1).

Example 59(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.015 g, 10%) byusing a procedure that is similar to the one described for example 7from intermediate 86 (0.080 g, 0.254 mmol), intermediate 23b (0.077 g,0.254 mmol), tris(4-methoxyphenyl)phosphine (0.134 g, 0.381 mmol), THF(2 ml) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol). MP:242-245° C. Enantiomeric excess 96.21%. Mass: 599.1 (M⁺+1).

Example 604-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzenesulfonamide

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzenesulfonamide:The title compound was obtained as brown solid (0.060 g, 38%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-sulfamoylphenylboronic acid (0.083 g, 0.411 mmol),sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 232-235° C. Mass: 575.3 (M⁺+1).

Example 61 methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carboxylate

methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carboxylate:The title compound was obtained as brown solid (0.070 g, 46%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 5-(methoxycarbonyl)thiophen-3-ylboronic acid (0.076 g,0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 227-230° C. Mass: 560.2 (M⁺+1).

Example 622-(1-(4-amino-3-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.045 g, 32%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 5-methylthiophen-2-ylboronic acid (0.092 g, 0.411 mmol),sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 223-226° C. Mass: 516.1 (M⁺+1).

Example 632-(1-(4-amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.030 g, 20%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid (0.100 g,0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 303-306° C. Mass: 536.4 (M⁺+1).

Example 64 methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorobenzoate

methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorobenzoate:The title compound was obtained as brown solid (0.017 g, 8%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.0 ml), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.109 g,0.550 mmol), sodium carbonate (0.116 g, 1.10 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.060 g, 0.073 mmol). MP: 258-260° C. Mass: 572.4 (M⁺+1).

Example 652-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyl-4H-chromen-4-one

2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyl-4H-chromen-4-one: Toa solution of intermediate 93 (0.190 g, 0.639 mmol), tert-butanol (2 ml)N,N-diisopropylethylamine (0.23 ml, 1.32 mmol) and 6-chloropurine (0.079g, 0.511 mmol) were added and heated to reflux for 48 h. The reactionmixture was concentrated, quenched with water, extracted with ethylacetate, dried with sodium sulphate and concentrated. The crude productwas purified by column chromatography with methanol:ethyl acetate toafford the title compound as brown solid (0.030 g, 140% yield). MP:210-212° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.83 (s, 1H), 8.19 (s,1H), 8.12 (s, 1H), 7.20-7.14 (m, 6H), 6.69 (d, J=8.1 Hz, 1H), 6.59 (t,J=8.7 Hz, 1H), 5.57 (m, 1H), 2.98 (m, 1H), 1.89 (m, 2H), 0.78 (t, J=7.1Hz, 3H).

Example 662-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 27 (0.200 g, 0.364 mmol) in THF (4 ml)propargyl alcohol (0.025 ml, 0.437 mmol) was added and degassed withnitrogen for 10 min. Copper (I) iodide (7 mg, 0.036 mmol),tetrakistriphenylphosphine palladium (0 (0.042 g, 0.036 mmol) anddiisopropylamine (0.23 ml, 1.82 mmol) were added and again degassed for10 min. and heated to reflux. After 4 h, the reaction mixture wasfiltered through celite, washed with ethyl acetate, dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:pet. ether to afford the titlecompound as brown solid (0.050 g, 29% yield). MP: 220-222° C. Mass:474.3 (M⁺+1).

Example 67(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methyl benzenesulfonate

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate: To example 7 (0.100 g, 0.174 mmol) inisopropanol (4 ml), p-toluenesulphonic acid (0.037 g, 0.192 mmol) wasadded and refluxed for 1 h. The reaction mixture was concentrated,co-distilled with pet. ether and dried. To the residue water (3 ml) wasadded and stirred for 30 min. The solid was filtered, washed with pet.ether and dried under vacuum to afford the title compound as off-whitesolid (0.110 g, 82%). MP: 152-155° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.15 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.64 (dt, J=8.4, 5.4 Hz, 1H), 7.42(dd, J=11.3, 2.0 Hz, 1H), 7.34 (m, 3H), 7.22 (d, J=8.0 Hz, 2H), 7.16 (t,J=8.6 Hz, 1H), 7.08-6.97 (m, 3H), 6.88 (m, 1H), 6.08 (q, J=7.1 Hz, 1H),4.687 (quintet, J=6.0 Hz, 1H), 2.37 (s, 3H), 2.02 (d, J=7.2 Hz, 3H),1.43 (d, J=6.1 Hz, 6H).

Example 68(+)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(+)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.090 g, 43%) byusing a procedure that is similar to the one described for example 7from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol),intermediate 23b (0.150 g, 0.494 mmol), triphenylphosphine (0.194 g,0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (1.8 ml) and dichloromethane (5 ml). MP: 194-197° C. Enantiomericexcess: 99.62%. [α]²⁵ _(D) 142.00 (c=1, CHCl₃). Mass: 420.1 (M⁺+1).

Example 692-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.081 g, 39%) byusing a procedure that is similar to the one described for example 7from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol),intermediate 23 (0.150 g, 0.494 mmol), triphenylphosphine (0.194 g,0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (1.3 ml) and dichloromethane (8 ml). MP: 247-249° C. Mass: 420.1(M⁺+1).

Example 70(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.022 g, 11%) byusing a procedure that is similar to the one described for example 7from intermediate 86 (0.100 g, 0.329 mmol), intermediate 23a (0.100 g,0.329 mmol), tris(4-methoxyphenyl)phosphine (0.174 g, 0.494 mmol), THF(2 ml) and diisopropylazodicarboxylate (0.1 ml, 0.494 mmol). MP:243-246° C. Enantiomeric excess 85.4%, Mass: 599.4 (M⁺+1).

Example 712-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.070 g, 46%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-methoxy-3,5-dimethylphenylboronic acid (0.074 g, 0.411mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 232-235° C. Mass: 554.0 (M⁺+1).

Example 722-(1-(4-amino-3-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.062 g, 42%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-(methoxymethyl)phenylboronic acid (0.068 g, 0.411mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 204-207° C. Mass: 540.3 (M⁺+1).

Example 732-(1-(4-amino-3-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.052 g, 36%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), imidazo[1,2-a]pyridin-6-ylboronic acid (0.066 g, 0.411mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 317-320° C. Mass: 536.3 (M⁺+1).

Example 74 tert-butyl(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamate

tert-butyl(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamate:The title compound was obtained as brown solid (0.100 g, 63%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 5-((tert-butoxycarbonylamino)methyl)furan-2-ylboronicacid (0.099 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 163-166° C. Mass: 615.7 (M⁺+1).

Example 752-(1-(4-amino-3-(2,4-dimethylthiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(2,4-dimethylthiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.050 g, 39%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole(0.098 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 252-255° C. Mass: 531.3 (M⁺+1).

Example 762-(1-(4-amino-3-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.047 g, 29%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml),4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine(0.127 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 193-196° C. Mass: 601.6 (M⁺+1).

Example 772-(1-(4-amino-3-(4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.071 g, 44%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 4-(5-amino-1,3,4-thiadiazol-2-yl)phenylboronic acid(0.091 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 202-205° C. Mass: 595.6 (M⁺+1).

Example 78(−)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(−)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.075 g, 36%) byusing a procedure that is similar to the one described for example 7from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol),intermediate 23a (0.150 g, 0.494 mmol), triphenylphosphine (0.194 g,0.741 mmol), THF (8 ml) and diisopropylazodicarboxylate (0.15 ml, 0.749mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (0.50 ml) and dichloromethane (6 ml). MP: 205-208° C. Enantiomericexcess: 100%, [α]²⁵ _(D) −180.47 (c=1, CHCl₃). Mass: 420.5 (M⁺+1).

Example 792-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.039 g, 26%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml),1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.112 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 220-224° C. Mass: 564.0 (M⁺+1).

Example 802-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.060 g, 40%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml),2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole(0.112 g, 0.411 mmol), sodium carbonate (0.058 g, 0.55 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.045 g, 0.055 mmol). MP: 232-235° C. Mass: 563.8 (M⁺).

Example 81N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)isobutyramide

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)isobutyramide:The title compound was obtained as brown solid (0.061 g, 37%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 95 (0.125 g, 0.411 mmol), sodium carbonate(0.058 g, 0.55 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.045 g, 0.055 mmol). MP: 249-252° C. Mass: 598.8(M⁺).

Example 82N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamide

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamide:The title compound was obtained as brown solid (0.030 g, 19%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.274 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 97 (0.114 g, 0.411 mmol), sodium carbonate(0.058 g, 0.55 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.045 g, 0.055 mmol). MP: 220-223° C. Mass:571.198.8 (M⁺+1).

Example 832-(1-(4-(dimethylamino)-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-(dimethylamino)-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale-yellow solid (0.050 g, 13%) byusing a procedure that is similar to the one described for example 7from intermediate 99 (0.200 g, 0.630 mmol), intermediate 23 (0.229 g,0.756 mmol), tris-4-methoxytriphenylphosphine (0.288 g, 0.819 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.945 mmol). MP:122-124° C. Mass: 600.2 (M⁺+1).

Example 845-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.038 g, 25%) by using aprocedure that is similar to the one described for example 9 fromintermediate 101 (0.150 g, 0.267 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 12 (0.110 g, 0.401 mmol), sodium carbonate(0.057 g, 0.535 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.053 mmol). MP: 193-196° C. Mass: 586.3(M⁺+1).

Example 855-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.120 g, 46%) byusing a procedure that is similar to the one described for example 7from intermediate 104 (0.150 g, 0.402 mmol), intermediate 23 (0.146 g,0.483 mmol), tris-4-methoxytriphenylphosphine (0.184 g, 0.523 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.604 mmol). MP:116-119° C. Mass: 641.8 (M⁺+1).

Example 86N-(2-fluoro-4-(1-(1-(5-fluoro-3-(4-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide

N-(2-fluoro-4-(1-(1-(5-fluoro-3-(4-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide:The title compound was obtained as brown solid (0.030 g, 18%) by using aprocedure that is similar to the one described for example 9 fromintermediate 105 (0.150 g, 0.243 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 95 (0.111 g, 0.365 mmol), sodium carbonate(0.051 g, 0.487 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.040 g, 0.048 mmol). MP: 165-167° C. Mass: 669.2(M⁺+1).

Example 87N-(2-fluoro-4-(1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide

N-(2-fluoro-4-(1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide:The title compound was obtained as brown solid (0.050 g, 31%) by using aprocedure that is similar to the one described for example 9 fromintermediate 106 (0.150 g, 0.243 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 95 (0.111 g, 0.365 mmol), sodium carbonate(0.051 g, 0.487 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.040 g, 0.048 mmol). MP: 168-170° C. Mass: 669.2(M⁺+1).

Example 88(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onesulphate

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onesulphate: The title compound was obtained as off-white solid (0.120 g,68%) by using a procedure that is similar to the one described forexample 67 from example 6a (0.150 g, 0.262 mmol), isopropanol (6 ml),sulphuric acid (0.028 g, 0.288 mmol). MP: 205-207° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): δ 8.12 (s, 1H), 7.64 (dt, J=8.4, 5.4 Hz, 1H), 7.41 (dd,J=11.2, 2.0 Hz, 1H), 7.29 (m, 3H), 7.15 (t, J=8.3 Hz, 1H), 7.08 (m, 2H),6.97 (d, J=6.9 Hz, 1H), 6.89 (d, J=7.1 Hz, 1H), 6.07 (q, J=6.9 Hz, 1H),4.68 (quintet, J=6.1 Hz, 1H), 2.01 (d, J=7.1 Hz, 3H), 1.42 (d, J=6.1 Hz,6H).

Example 89(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onebenzenesulfonate

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onebenzenesulfonate: The title compound was obtained as off-white solid(0.120 g, 62%) by using a procedure that is similar to the one describedfor example 67 from example 6a (0.150 g, 0.262 mmol), isopropanol (6ml), benzenesulphonic acid (0.045 g, 0.288 mmol). MP: 172-174° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): δ 8.14 (s, 1H), 7.92 (dd, J=6.8, 1.7 Hz, 2H),7.64 (dt, J=8.4, 5.4 Hz, 1H), 7.42-7.28 (m, 7H), 7.16 (t, J=8.3 Hz, 1H),7.11 (m, 3H), 6.87 (d, J=7.1 Hz, 1H), 6.08 (q, J=7.0 Hz, 1H), 4.68(quintet, J=6.1 Hz, 1H), 2.02 (d, J=7.1 Hz, 3H), 1.43 (d, J=6.0 Hz, 6H).

Example 90(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onecamphorsulphonate

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onecamphorsulphonate: The title compound was obtained as off-white solid(0.120 g, 57%) by using a procedure that is similar to the one describedfor example 67 from example 6a (0.150 g, 0.262 mmol), isopropanol (6ml), camphorsulphonic acid (0.066 g, 0.288 mmol). MP: 190-193° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): δ 8.23 (s, 1H), 7.64 (dt, J=8.4, 5.4 Hz, 1H),7.42 (dd, J=11.2, 2.1 Hz, 1H), 7.35 (m, 3H), 7.16 (t, J=8.4 Hz, 1H),7.08 (m, 3H), 6.92 (d, J=8.3 Hz, 1H), 6.08 (q, J=7.1 Hz, 1H), 4.68(quintet, J=6.1 Hz, 1H), 3.36 (d, J=4.4 Hz, 1H), 2.95 (d, J=4.6 Hz, 1H),2.59 (m, 1H), 2.35 (m, 1H), 2.09 (m, 2H), 2.02 (d, J=7.2 Hz, 3H),1.93-1.83 (m, 3H), 1.43 (d, J=6.1 Hz, 6H), 1.07 (s, 3H), 0.84 (s, 3H).

Example 912-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.120 g, 30%) by using aprocedure that is similar to the one described for example 9 fromintermediate 107 (0.400 g, 0.708 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), 1-boc-pyrazole-4-boronic acid (0.220 g, 1.06 mmol),sodium carbonate (0.220 g, 2.12 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.115 g, 0.141 mmol). MP: 135-138° C. Mass: 552.0 (M⁺+1).

Example 922-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as brown solid (0.045 g, 27%) by using aprocedure that is similar to the one described for example 9 fromintermediate 108 (0.150 g, 0.285 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 61 (0.130 g, 0.427 mmol), sodium carbonate(0.060 g, 0.570 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.046 g, 0.057 mmol). MP: 256-258° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt, J=8.4, 5.5 Hz, 1H),7.40-7.32 (m, 2H), 7.23 (m, 6H), 7.09 (m, 2H), 6.09 (q, J=7.1 Hz, 1H),5.38 (s, 2H), 3.91 (t, J=4.5 Hz, 4H), 3.18 (t, J=4.7 Hz, 4H), 1.98 (d,J=7.1 Hz, 3H).

Example 932-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.040 g, 24%) by using aprocedure that is similar to the one described for example 9 fromintermediate 34 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3.0 ml),water (1.5 ml), intermediate 61 (0.127 g, 0.412 mmol), sodium carbonate(0.058 g, 0.550 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.045 g, 0.055 mmol). MP: 240-242° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): δ 8.26 (s, 1H), 7.60 (dt, J=8.3, 5.5 Hz, 1H), 7.40(m, 2H), 7.28 (m, 3H), 7.09-6.99 (m, 4H), 6.06 (q, J=7.2 Hz, 1H), 5.45(s, 2H), 3.91 (t, J=4.5 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 1.99 (d, J=7.1Hz, 3H).

Example 94(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.033 g, 10%) byusing a procedure that is similar to the one described for example 7from intermediate 13 (0.199 g, 0.692 mmol), intermediate 113 (0.175 g,0.577 mmol), tris-4-methoxytriphenylphosphine (0.305 g, 0.865 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.17 ml, 0.865 mmol). MP:192-194° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.58 (dt,J=8.4, 5.4 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.37 (d, J=8.4 Hz,1H), 7.23 (m, 2H), 7.15 (t, J=8.3 Hz, 1H), 7.07 (m, 3H), 6.04 (q, J=7.1Hz, 1H), 5.42 (s, 2H), 4.65 (quintet, J=6.2 Hz, 1H), 1.99 (d, J=7.1 Hz,3H), 1.42 (d, J=6.1 Hz, 6H). Enantiomeric excess: 68.2% as determined byHPLC on a chiralpak AD-H column, enriched in the fast eluting isomer(retention time=10.43 min.).

Example 95(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.071 g, 18%) byusing a procedure that is similar to the one described for example 7from intermediate 13 (0.277 g, 0.791 mmol), intermediate 114 (0.200 g,0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.989 mmol), THF(4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP:209-212° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.26 (s, 1H), 7.61 (dt,J=8.4, 5.4 Hz, 1H), 7.44 (dd, J=11.4, 2.0 Hz, 1H), 7.37 (dd, J=8.3, 1.0Hz, 1H), 7.23 (m, 2H), 7.15 (t, J=8.4 Hz, 1H), 7.07 (m, 3H), 6.06 (q,J=7.1 Hz, 1H), 5.42 (s, 2H), 4.66 (quintet, J=6.1 Hz, 1H), 1.99 (d,J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H). Enantiomeric excess: 66% asdetermined by HPLC on a chiralpak AD-H column, enriched in the lateeluting isomer (retention time=15.96 min.).

Example 96(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one: Thetitle compound was obtained as pale yellow (0.018 g, 5%) by using aprocedure that is similar to the one described for example 7 fromintermediate 39 (0.204 g, 0.692 mmol), intermediate 113 (0.175 g, 0.577mmol), tris-4-methoxytriphenylphosphine (0.305 g, 0.865 mmol), THF (3ml) and diisopropylazodicarboxylate (0.17 ml, 0.865 mmol). MP: 246-248°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.28 (s, 1H), 7.61 (m, 2H), 7.47(m, 2H), 7.22 (m, 3H), 7.08 (m, 3H), 6.82 (t, J=73 Hz, 1H), 6.08 (q,J=7.1 Hz, 1H), 5.43 (s, 2H), 1.99 (d, J=7.1 Hz, 3H). Enantiomericexcess: 38.4% as determined by HPLC on a chiralpak AD-H column, enrichedin the fast eluting isomer (retention time=10.34 min.).

Example 97(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one: Thetitle compound was obtained as pale yellow solid (0.045 g, 12%) by usinga procedure that is similar to the one described for example 7 fromintermediate 39 (0.233 g, 0.791 mmol), intermediate 114 (0.200 g, 0.659mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.989 mmol), THF (4ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP: 242-244°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.29 (s, 1H), 7.61 (m, 2H), 7.47(m, 2H), 7.25 (m, 3H), 7.08 (m, 3H), 6.82 (t, J=73 Hz, 1H), 6.06 (q,J=7.1 Hz, 1H), 5.39 (s, 2H), 1.99 (d, J=7.1 Hz, 3H). Enantiomericexcess: 46.8% as determined by HPLC on a chiralpak AD-H column, enrichedin the late eluting isomer (retention time=18.36 min.).

Example 982-(1-(4-(dimethylamino)-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-(dimethylamino)-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.085 g, 31%) byusing a procedure that is similar to the one described for example 6from intermediate 117 (0.150 g, 0.438 mmol), DMF (2 ml), potassiumcarbonate (0.073 g, 0.525 mmol) and intermediate 22 (0.224 g, 0.0.613mmol). MP: 208-210° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.23 (s, 1H),7.62 (dt, J=8.4, 5.5 Hz, 1H), 7.34-7.28 (m, 4H), 7.06-6.92 (m, 4H), 6.83(d, J=8.1 Hz, 1H), 6.10 (q, J=7.1 Hz, 1H), 3.91 (t, J=4.5 Hz, 4H), 3.16(t, J=4.6 Hz, 4H), 2.92 (s, 6H), 1.96 (d, J=7.1 Hz, 3H).

Example 995-fluoro-2-(1-(3-(3-fluoro-4-morpholinophenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

5-fluoro-2-(1-(3-(3-fluoro-4-morpholinophenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.075 g, 27%) byusing a procedure that is similar to the one described for example 6from intermediate 118 (0.150 g, 0.456 mmol), DMF (2 ml), potassiumcarbonate (0.075 g, 0.540 mmol) and intermediate 22 (0.237 g, 0.0.630mmol). MP: 238-240° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.30 (s, 1H),7.62 (dt, J=8.4, 5.5 Hz, 1H), 7.36-7.27 (m, 4H), 7.06-6.98 (m, 4H), 6.89(d, J=10.6 Hz, 1H), 6.04 (q, J=7.2 Hz, 1H), 5.32 (q, J=4.8 Hz, 1H), 3.92(t, J=4.5 Hz, 4H), 3.19 (t, J=4.6 Hz, 4H), 3.09 (d, J=4.9 Hz, 3H), 1.97(d, J=7.2 Hz, 3H).

Example 100(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as off-white solid (0.050 g, 14%) byusing a procedure that is similar to the one described for example 7from intermediate 13 (0.212 g, 0.738 mmol), intermediate 115 (0.175 g,0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP:205-208° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt,J=8.4, 5.4 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.37-7.29 9 m, 4H),7.23 (m, 3H), 7.14 (t, J=8.4 Hz, 1H), 7.04 (t, J=10.1 Hz, 1H), 6.08 (q,J=7.1 Hz, 1H), 5.42 (s, 2H), 4.65 (quintet, J=6.1 Hz, 1H), 1.98 (d,J=7.2 Hz, 3H), 1.42 (d, J=6.1 Hz, 6H). Enantiomeric excess: 81% asdetermined by HPLC on a chiralpak AD-H column, enriched in the fasteluting isomer (retention time=10.12 min.).

Example 101(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

(S)/(R)-22-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as off-white solid (0.067 g, 19%) byusing a procedure that is similar to the one described for example 7from intermediate 13 (0.212 g, 0.738 mmol), intermediate 116 (0.175 g,0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP:185-188° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.23 (s, 1H), 7.60 (dt,J=8.4, 5.5 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.37-7.29 (m, 4H),7.23 (m, 3H), 7.14 (t, J=8.3 Hz, 1H), 7.04 (t, J=9.9 Hz, 1H), 6.08 (q,J=7.1 Hz, 1H), 5.43 (s, 2H), 4.64 (quintet, J=6.0 Hz, 1H), 1.98 (d,J=7.2 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H). Enantiomeric excess: 73.5% asdetermined by HPLC on a chiralpak AD-H column, enriched in the lateeluting isomer (retention time=13.20 min.).

Example 102(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as pale yellow solid (0.069 g, 20%) byusing a procedure that is similar to the one described for example 7from intermediate 39 (0.218 g, 0.738 mmol), intermediate 115 (0.175 g,0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP:247-250° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.26 (s, 1H), 7.60 (m,2H), 7.47 (m, 2H), 7.35 (m, 3H), 7.24 (m, 3H), 7.05 (t, J=10.1 Hz, 1H),6.81 (t, J=73 Hz, 1H), 6.10 (q, J=7.1 Hz, 1H), 5.39 (s, 2H), 1.99 (d,J=7.1 Hz, 3H). Enantiomeric excess: 64.7% as determined by HPLC on achiralpak AD-H column, enriched in the fast eluting isomer (retentiontime=9.78 min.).

Example 103(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one:The title compound was obtained as pal yellow solid (0.033 g, 6%) byusing a procedure that is similar to the one described for example 7from intermediate 39 (0.218 g, 0.738 mmol), intermediate 116 (0.175 g,0.615 mmol), tris-4-methoxytriphenylphosphine (0.325 g, 0.923 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.18 ml, 0.923 mmol). MP:217-220° C. ¹H-NMR (6 ppm, CDCl₃, 400 MHz): δ 8.26 (s, 1H), 7.60 (m,2H), 7.47 (m, 2H), 7.35 (m, 3H), 7.26 (m, 3H), 7.05 (t, J=9.7 Hz, 1H),6.81 (t, J=73 Hz, 1H), 6.08 (q, J=7.2 Hz, 1H), 5.38 (s, 2H), 1.99 (d,J=7.2 Hz, 3H). Enantiomeric excess: 47.4% as determined by HPLC on achiralpak AD-H column, enriched in the late eluting isomer (retentiontime=14.01 min.).

Example 104(+)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

(+)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.212 g, 54%) byusing a procedure that is similar to the one described for example 7from intermediate 119 (0.218 g, 0.725 mmol), intermediate 23b (0.200 g,0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.980 mmol), THF(4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP:199-202° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.30 (s, 1H), 7.61 (dt,J=8.4, 5.4 Hz, 1H), 7.39 (dd, J=11.5, 2.1 Hz, 1H), 7.31 (m, 3H), 7.15(t, J=8.4 Hz, 1H), 7.06 (m, 3H), 6.90 (t, J=9.9 Hz, 1H), 6.04 (q, J=7.1Hz, 1H), 5.31 (q, J=4.9 Hz, 1H), 4.66 (quintet, J=6.1 Hz, 1H), 3.09 (d,J=4.9 Hz, 3H), 1.97 (d, J=7.1 Hz, 3H), 1.43 (d, J=6.1 Hz, 6H).Enantiomeric excess: 96.5% as determined by HPLC on a chiralpak AD-Hcolumn, enriched in the fast eluting isomer (retention time=8.91 min.),[α]²⁵ _(D) 181.67 (c=1, CHCl₃).

Example 105(−)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

(−)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.201 g, 52%) byusing a procedure that is similar to the one described for example 7from intermediate 119 (0.218 g, 0.725 mmol), intermediate 23a (0.200 g,0.659 mmol), tris-4-methoxytriphenylphosphine (0.348 g, 0.980 mmol), THF(4 ml) and diisopropylazodicarboxylate (0.19 ml, 0.989 mmol). MP:216-218° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.30 (s, 1H), 7.61 (dt,J=8.4, 5.4 Hz, 1H), 7.39 (dd, J=11.5, 2.1 Hz, 1H), 7.31 (m, 2H), 7.27(m, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.05 (m, 3H), 6.90 (t, J=9.8 Hz, 1H),6.06 (q, J=7.1 Hz, 1H), 5.30 (q, J=4.7 Hz, 1H), 4.99 (quintet, J=6.2 Hz,1H), 3.09 (d, J=4.9 Hz, 3H), 1.97 (d, J=7.2 Hz, 3H), 1.43 (d, J=6.0 Hz,6H). Enantiomeric excess: 88.4% as determined by HPLC on a chiralpakAD-H column, enriched in the late eluting isomer (retention time=1.22min.) [α]²⁵ _(D) 172.64 (c=1, CHCl₃).

Example 1062-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.180 g, 63%) byusing a procedure that is similar to the one described for example 6from 2-fluoro-9H-purin-6-amine (0.100 g, 0.653 mmol), DMF (2 ml),potassium carbonate (0.108 g, 0.783 mmol) and intermediate 22 (0.330 g,0.0.914 mmol). MP: 255-258° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.42 (s,1H), 7.83 (m, 3H), 7.53 (d, J=8.6 Hz, 1H), 7.49 (m, 1H), 7.28-7.13 (m,4H), 5.52 (q, J=7.1 Hz, 1H), 1.87 (d, J=7.2 Hz, 3H). Mass: 437.7 (M⁺).

Example 1072-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one

2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.120 g, 42%) byusing a procedure that is similar to the one described for example 6from 2-fluoro-9H-purin-6-amine (0.100 g, 0.653 mmol), DMF (2 ml),potassium carbonate (0.108 g, 0.783 mmol) and intermediate 31 (0.330 g,0.0.914 mmol). MP: 272-275° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.41 (s,1H), 7.83 (m, 3H), 7.52 (d, J=8.6 Hz, 1H), 7.35-7.22 (m, 5H), 5.49 (q,J=7.2 Hz, 1H), 1.87 (d, J=7.2 Hz, 3H).

Example 1085-fluoro-3-(4-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one

5-fluoro-3-(4-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.090 g, 47%) byusing a procedure that is similar to the one described for example 6from 4-(9H-purin-6-yl)morpholine (0.080 g, 0.389 mmol for preparationsee Tetrahedron, 2007, 63, 5323-5328), DMF (1.5 ml), potassium carbonate(0.064 g, 0.467 mmol) and intermediate 31 (0.185 g, 0.0.506 mmol). MP:186-189° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.26 (s, 1H), 8.04 (s, 1H),7.60 (dt, J=8.4, 5.4 Hz, 1H), 7.37 (m, 2H), 7.26 (m, 3H), 7.04 (t, J=9.4Hz, 1H), 5.89 (q, J=7.3 Hz, 1H), 4.29 br s, 4H), 3.84 (t, J=4.9 Hz, 4H),1.90 (d, J=7.3 Hz, 3H).

Example 1095-fluoro-3-(4-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one

5-fluoro-3-(4-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.012 g, 8%) byusing a procedure that is similar to the one described for example 6from 6-(4-methylpiperazin-1-yl)-9H-purine (0.060 g, 0.274 mmol), DMF(1.5 ml), potassium carbonate (0.046 g, 0.329 mmol) and intermediate 31(0.130 g, 0.0.357 mmol). MP: 157-160° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.25 (s, 1H), 8.04 (s, 1H), 7.62 (dt, J=8.4, 5.4 Hz, 1H), 7.37 (m, 2H),7.25 (m, 3H), 7.07 (dt, J=9, 0.7 Hz, 1H), 5.90 (q, J=7.2 Hz, 1H), 4.31br s, 4H), 2.54 (br s, 4H), 2.34 (s, 3H), 1.89 (d, J=7.3 Hz, 3H).

Example 1102-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a brown solid (0.045 g, 20%) by usinga procedure that is similar to the one described for example 6 fromN,N-dimethyl-9H-purin-6-amine (0.080 g, 0.490 mmol for preparation seeJ. Het. Chem. 1983, 20, 295-199), DMF (2 ml), potassium carbonate (0.081g, 0.588 mmol) and intermediate 22 (0.250 g, 0.0.686 mmol). MP: 166-169°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.26 (s, 1H), 8.00 (s, 1H), 7.61 (dt,J=8.5, 5.5 Hz, 1H), 7.48 (dd, J=7.9, 5.9 Hz, 1H), 7.22 (m, 4H), 7.07(dt, J=8.3, 0.8 Hz, 1H), 5.87 (q, J=7.2 Hz, 1H), 3.52 (s, 6H), 1.90 (d,J=7.3 Hz, 3H).

Example 1112-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

5-fluoro-3-(3-fluorophenyl)-2-(1-(6-(methylamino)-9H-purin-9-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.020 g, 9%) byusing a procedure that is similar to the one described for example 6from N-methyl-9H-purin-6-amine (0.080 g, 0.534 mmol for preparation seeBull. Soc. Jpn. 1986, 62, 3155-3160.), DMF (2 ml), potassium carbonate(0.087 g, 0.641 mmol) and intermediate 22 (0.273 g, 0.0.748 mmol). MP:207-209° C. Mass: 433.9 (M⁺).

Example 1125-fluoro-3-(3-fluorophenyl)-2-(1-(3-(3-methyl-1H-indazol-6-yl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one

5-fluoro-3-(3-fluorophenyl)-2-(1-(3-(3-methyl-1H-indazol-6-yl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.050 g, 25%) by using aprocedure that is similar to the one described for example 9 fromintermediate 106 (0.200 g, 0.325 mmol), 1,2-dimethoxyethane (3 ml),water (1.5 ml), tert-butyl3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.174 g, 0.487 mmol), sodium carbonate (0.103 g, 0.975 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.053 g,0.065 mmol) MP: 183-186° C. Mass: 619.8 (M⁺+1).

Example 1132-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.018 g, 10%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 123 (0.134 g, 0.412 mmol), sodium carbonate(0.058 g, 0.550 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol) MP: 250-253° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.25 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.59 (m,2H), 7.27 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 7.05-6.99 (m, 4H), 6.06 (q,J=7.1 Hz, 1H), 5.38 (s, 2H), 3.92 (t, J=4.5 Hz, 4H), 3.14 (t, J=4.6 Hz,4H), 1.99 (d, J=7.2 Hz, 3H).

Example 114 (+)2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(+)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.083 g, 30%) byusing a procedure that is similar to the one described for example 7from intermediate 84 (0.150 g, 0.529 mmol), intermediate 23b (0.145 g,0.481 mmol), tris-4-methoxytriphenylphosphine (0.254 g, 0.721 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.14 ml, 0.721 mmol). MP:217-220° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.61 (dt,J=8.4, 5.4 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.97 (m, 4H), 6.92(d, J=9.4 Hz, 1H), 6.07 (q, J=7.1 Hz, 1H), 5.42 (s, 2H), 4.63 (quintet,J=6.0 Hz, 1H), 2.28 (s, 3H), 1.97 (d, J=7.1 Hz, 3H), 1.39 (d, J=6.0 Hz,6H). Enantiomeric excess: 100% as determined by HPLC on a chiralpak AD-Hcolumn, enriched in the fast eluting isomer (retention time=9.36 min.)[α]²⁵ _(D) 176.04 (c=1, CHCl₃).

Example 115 (−)2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(−)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.066 g, 28%) byusing a procedure that is similar to the one described for example 7from intermediate 84 (0.128 g, 0.453 mmol), intermediate 23a (0.125 g,0.412 mmol), tris-4-methoxytriphenylphosphine (0.217 g, 0.618 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.618 mmol). MP:221-224° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.61 (dt,J=8.4, 5.5 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.95 (m, 4H), 6.92(d, J=9.5 Hz, 1H), 6.05 (q, J=7.1 Hz, 1H), 5.40 (s, 2H), 4.62 (quintet,J=6.0 Hz, 1H), 2.28 (s, 3H), 1.99 (d, J=7.2 Hz, 3H), 1.39 (d, J=6.0 Hz,6H). Enantiomeric excess: 99.6% as determined by HPLC on a chiralpakAD-H column, enriched in the late eluting isomer (retention time=11.43min.) [α]²⁵ _(D) −183.59 (c=1, CHCl₃).

Example 116(S)/(R)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale yellow solid (0.044 g, 12%) byusing a procedure that is similar to the one described for example 7from intermediate 104 (0.243 g, 0.652 mmol), intermediate 23a (0.180 g,0.593 mmol), tris-4-methoxytriphenylphosphine (0.272 g, 0.771 mmol), THF(3 ml) and diisopropylazodicarboxylate (0.17 ml, 0.890 mmol). MP:136-138° C. Mass: 642.0 (M⁺). Enantiomeric excess: 91.6% as determinedby HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer(retention time=10.27 min.).

Example 1172-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.039 g, 24%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 125 (0.107 g, 0.412 mmol), sodium carbonate(0.088 g, 0.825 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol). MP: 207-210° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.24 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.62 (dt,J=8.3, 5.3 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.31 (m, 2H), 7.10 (d,J=8.6 Hz, 1H), 7.06 (m, 3H), 6.92 (d, J=9.6 Hz, 1H), 6.06 (q, J=7.2 Hz,1H), 5.38 (s, 2H), 4.66 (quintet, J=6.1 Hz, 1H), 1.99 (d, J=7.2 Hz, 3H).1.44 (d, J=6.0 Hz, 6H).

Example 1182-(1-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.017 g, 11%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 127 (0.107 g, 0.412 mmol), sodium carbonate(0.088 g, 0.825 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol). MP: 215-217° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.26 (s, 1H), 7.81 (m, 2H), 7.63 (m, 2H), 7.30 (m,2H), 7.06 (m, 3H), 6.94 (d, J=9.3 Hz, 1H), 6.10 (q, J=7.1 Hz, 1H), 5.48(s, 2H), 2.70 (s, 3H), 2.01 (d, J=7.1 Hz, 3H).

Example 1195-fluoro-3-(3-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one

5-fluoro-3-(3-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a yellow solid (0.060 g, 31%) byusing a procedure that is similar to the one described for example 6from 4-(9H-purin-6-yl)morpholine (0.080 g, 0.389 mmol for preparationsee J. Med. Chem. 2010, 53, 8421-8439), DMF (1.5 ml), potassiumcarbonate (0.064 g, 0.467 mmol) and intermediate 22 (0.185 g, 0.0.506mmol). MP: 239-241° C. Mass: 490.1 (M⁺+1).

Example 1202-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-5-morpholino-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-5-morpholino-4H-chromen-4-one:To a solution of example 6 (0.100 g, 0.174 mmol) in dioxan (1 ml),morpholine (0.015 g, 0.174 mmol) was added and refluxed for 3 h. Thereaction mixture was quenched with water, the product precipitated wasfiltered, washed with water, petroleum ether and dried under vacuum toafford the title compound as a pale yellow solid (0.090 g, 80%). MP:227-229° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.23 (s, 1H), 7.54 (t, J=8.3Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.29 (m,1H), 7.14 (t, J=8.4 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.98 (m, 2H), 6.85(m, 2H), 5.98 (q, J=7.2 Hz, 1H), 5.38 (s, 2H), 4.64 (quintet, J=6.1 Hz,1H), 3.90 (t, J=4.2 Hz, 4H), 3.07 (t, J=4.2 Hz, 4H), 1.96 (d, J=7.2 Hz,3H), 1.42 (d, J=6.0 Hz, 6H). Mass: 638.8 (M⁺).

Example 1212-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-morpholino-3-phenyl-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-morpholino-3-phenyl-4H-chromen-4-one:To a solution of example 13 (0.040 g, 0.072 mmol) in dioxan (1 ml),morpholine (0.007 g, 0.072 mmol) was added and refluxed for 3 h. Thereaction mixture was quenched with water, the product precipitated wasfiltered, washed with water, petroleum ether and dried under vacuum toafford the title compound as a pale yellow solid (0.030 g, 67%). MP:211-214° C. Mass: 621.2 (M⁺+1).

Example 1226-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one

6-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one:The title compound was obtained as brown solid (0.045 g, 30%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 128 (0.106 g, 0.412 mmol), sodium carbonate(0.058 g, 0.550 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol). MP: 242-245° C. Mass: 551.0(M⁺+1).

Example 1235-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one

5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one:The title compound was obtained as brown solid (0.052 g, 35%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 129 (0.106 g, 0.412 mmol), sodium carbonate(0.058 g, 0.550 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol). MP: 293-296° C. Mass: 550.7(M⁺).

Example 1242-(1-(3-(4-acetyl-3-fluorophenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(3-(4-acetyl-3-fluorophenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.045 g, 29%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.150 g, 0.275 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 130 (0.106 g, 0.412 mmol), sodium carbonate(0.087 g, 0.825 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.044 g, 0.055 mmol). MP: 237-239° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.29 (s, 1H), 8.08 (t, J=7.7 Hz, 1H), 7.62 (m,3H), 7.32 (m, 2H), 7.07 (m, 3H), 6.92 (d, J=9.1 Hz, 1H), 6.09 (q, J=7.1Hz, 1H), 5.39 (s, 2H), 2.71 (d, J=4.8 Hz, 3H), 2.01 (d, J=7.1 Hz, 3H).

Example 1255-fluoro-3-(3-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one

5-fluoro-3-(3-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.052 g, 9%) byusing a procedure that is similar to the one described for example 6from 6-(4-methylpiperazin-1-yl)-9H-purine (0.240 g, 1.09 mmol forpreparation see Tetrahedron, 2007, 63, 5323-5328.), DMF (4.8 ml),potassium carbonate (0.182 g, 1.31 mmol) and intermediate 22 (0.522 g,0.1.429 mmol). MP: 199-201° C. Mass: 502.8 (M⁺).

Example 126(S)/(R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.036 g, 12%) byusing a procedure that is similar to the one described for example 7from intermediate 131 (0.196 g, 0.592 mmol), intermediate 23b (0.150 g,0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g, 0.741 mmol), THF(4 ml) and diisopropylazodicarboxylate (0.13 ml, 0.741 mmol). MP:256-258° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.24 (s, 1H), 7.71 (d,J=2.1 Hz, 1H), 7.62 (dt, J=8.4, 5.4 Hz, 1H), 7.55 (dd, J=8.2, 2.0 Hz,1H), 7.31 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 7.06 (m, 3H), 6.91 (d, J=9.7Hz, 1H), 6.08 (q, J=7.1 Hz, 1H), 5.43 (s, 2H), 3.92 (t, J=4.4 Hz, 4H),3.14 (d, J=4.5 Hz, 4H), 1.99 (d, J=7.2 Hz, 3H). Enantiomeric excess:98.8% as determined by HPLC on a chiralpak AD-H column, enriched in thefast eluting isomer (retention time=15.07 min.).

Example 127(S)/(R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.085 g, 28%) byusing a procedure that is similar to the one described for example 7from intermediate 131 (0.196 g, 0.592 mmol), intermediate 23a (0.150 g,0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g, 0.741 mmol), THF(4 ml) and diisopropylazodicarboxylate (0.13 ml, 0.741 mmol). MP:260-262° C. Mass: 616.9 (M⁺+1).

Enantiomeric excess: 96% as determined by HPLC on a chiralpak AD-Hcolumn, enriched in the late eluting isomer (retention time=22.42 min.).

Example 128N-(3-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide

N-(3-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide:The title compound was obtained as brown solid (0.050 g, 23%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), intermediate 132 (0.163 g, 0.549 mmol), sodium carbonate(0.116 g, 1.10 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.059 g, 0.073 mmol). MP: 259-261° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 9.90 (s, 1H), 8.09 (s, 1H), 7.83 (dt, J=6.6, 1.0Hz, 1H), 7.51 (m, 3H), 7.36-7.24 (m, 4H), 7.07 (dt, J=8.5, 2.5 Hz, 1H),6.93 (m, 2H), 5.99 (q, J=7.1 Hz, 1H), 3.04 (s, 3H), 1.88 (d, J=7.1 Hz,3H).

Example 129(S)/(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.020 g, 9%) byusing a procedure that is similar to the one described for example 7from N,N-dimethyl-9H-purin-6-amine (0.088 g, 0.543 mmol), intermediate23b (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g,0.741 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.14 ml, 0.741mmol). MP: 187-189° C. Mass: 448.0 (M⁺+1). Enantiomeric excess: 100% asdetermined by HPLC on a chiralpak AD-H column, enriched in the fasteluting isomer (retention time=11.76 min.).

Example 130(S)/(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as off-white solid (0.016 g, 7%) byusing a procedure that is similar to the one described for example 7from N,N-dimethyl-9H-purin-6-amine (0.088 g, 0.543 mmol), intermediate23a (0.150 g, 0.494 mmol), tris-4-methoxytriphenylphosphine (0.261 g,0.741 mmol), THF (4 ml) and diisopropylazodicarboxylate (0.14 ml, 0.741mmol). MP: 198-200° C. Mass: 447.7 (M⁺). Enantiomeric excess: 94.8% asdetermined by HPLC on a chiralpak AD-H column, enriched in the lateeluting isomer (retention time=19.68 min.).

Example 1312-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one

2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as pale-yellow solid (0.095 g, 33%) byusing a procedure that is similar to the one described for example 7from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.396 g, 0.831 mmol),intermediate 135 (0.210 g, 0.692 mmol), triphenylphosphine (0.272 g,1.03 mmol), THF (6 ml) and diisopropylazodicarboxylate (0.20 ml, 1.038mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (0.6 ml) and dichloromethane (3 ml). MP: 203-205° C. Mass: 419.7(M⁺).

Example 1322-(1-(4-amino-3-(4-ethoxy-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(4-ethoxy-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as brown solid (0.026 g, 12%) by using aprocedure that is similar to the one described for example 9 fromintermediate 27 (0.200 g, 0.366 mmol), 1,2-dimethoxyethane (3 ml), water(1.5 ml), 4-ethoxy-3-(trifluoromethyl)phenylboronic acid (0.128 g, 0.550mmol), sodium carbonate (0.116 g, 1.10 mmol) andbis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (0.059 g,0.073 mmol). MP: 225-227° C. Mass: 608.1 (M⁺+1).

Example 1332-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:The title compound was obtained as a off-white solid (0.062 g, 36%) byusing a procedure that is similar to the one described for example 6from intermediate 13 (0.080 g, 0.293 mmol), DMF (2 ml), potassiumcarbonate (0.081 g, 0.587 mmol) and intermediate 137 (0.130 g, 0.0.440mmol). MP: 241-243° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.25 (s, 1H),7.63 (dt, J=8.4, 5.4 Hz, 1H), 7.44 (dd, J=11.5, 2.0 Hz, 1H), 7.35 (m,3H), 7.14 (t, J=8.4 Hz, 1H), 7.06 (m, 3H), 6.92 (d, J=7.5 Hz, 1H), 5.85(dd, J=9.0, 6.6 Hz, 1H), 5.44 (s, 2H), 4.66 (quintet, J=6.2 Hz, 1H),2.64 (m, 1H), 2.46 (m, 1H), 1.42 (d, J=6.0 Hz, 6H), 0.91 (t, J=7.3 Hz,3H).

Example 134(S)/(R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one

(S)/(R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one: The title compound was obtained as pale-brownsolid (0.055 g, 25%) by using a procedure that is similar to the onedescribed for example 7 from intermediate 140 (0.245 g, 0.494 mmol),intermediate 23b (0.150 g, 0.494 mmol), triphenylphosphine (0.194 g,0.741 mmol), THF (7 ml) and diisopropylazodicarboxylate (0.16 ml, 0.741mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (0.6 ml) and dichloromethane (8 ml). MP: 186-189° C. Mass: 449.8(M⁺).

Example 135(S)/(R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one

(S)/(R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one: The title compound was obtained as pale-brownsolid (0.056 g, 34%) by using a procedure that is similar to the onedescribed for example 7 from intermediate 140 (0.179 g, 0.362 mmol),intermediate 23a (0.110 g, 0.494 mmol), triphenylphosphine (0.142 g,0.544 mmol), THF (7 ml) and diisopropylazodicarboxylate (0.11 ml, 0.544mmol), followed by the cleavage of the intermediate with trifluoroaceticacid (0.6 ml) and dichloromethane (7 ml). MP: 219-222° C. Mass: 449.8(M⁺).

Example 136(S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

(S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one:To a solution of intermediate 143 (0.22 g, 0.730 mmol), tert-butanol(1.5 ml) N,N-diisopropylethylamine (0.25 ml, 1.46 mmol) and6-chloro-2-fluoro-9H-purine (0.102 g, 0.663 mmol) were added and heatedto reflux for 248 h. The reaction mixture was concentrated, quenchedwith water, extracted with ethyl acetate, dried with sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol:ethyl acetate to afford the title compound as brown solid(0.042 g, 13% yield). MP: 183-186° C. Mass: 437.9 (M⁺). Enantiomericexcess: 33% as determined by HPLC on a chiralpak AD-H column, enrichedin the fast eluting isomer (retention time=7.21 min.).

Example 137(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one

(S)/(R)-22-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one:The title compound was obtained as off-white solid (0.030 g, 15%) byusing a procedure that is similar to the one described for example 7from intermediate 13 (0.122 g, 0.425 mmol), intermediate 149 (0.100 g,0.354 mmol), triphenylphosphine (0.140 g, 0.531 mmol), THF (1 ml) anddiisopropylazodicarboxylate (0.10 ml, 0.531 mmol). MP: 208-210° C. Mass:549.7 (M⁺). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.20 (s, 1H), 7.48 (t, J=7.6Hz, 1H), 7.43 (dd, J=11.4, 2.0 Hz, 1H), 7.34 (m, 5H), 7.20-7.10 (m, 4H),6.09 (q, J=7.1 Hz, 1H), 4.67 (quintet, J=6.1 Hz, 1H), 2.80 (s, 3H), 1.99(d, J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H). Enantiomeric excess: 99.34%as determined by HPLC on a chiralpak AD-H column, enriched in the fasteluting isomer (retention time=8.77 min).

Example 1382-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-o-tolyl-4H-chromen-4-one

2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-o-tolyl-4H-chromen-4-one: Thetitle compound was obtained as off-white solid (0.025 g, 20%) by using aprocedure that is similar to the one described for example 7 fromtert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.173 g, 0.362 mmol),intermediate 153 (0.090 g, 0.301 mmol), triphenylphosphine (0.119 g,0.451 mmol), THF (2.3 ml) and diisopropylazodicarboxylate (0.10 ml,0.451 mmol), followed by the cleavage of the intermediate withtrifluoroacetic acid (0.4 ml) and dichloromethane (2 ml). MP: 275-277°C. Mass: 416.0 (M⁺).

Biological Assay

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The pharmacologicalassays which can be been carried out with the compounds according to theinvention and/or their pharmaceutically acceptable salts is exemplifiedbelow.

Assay 1: Fluorescent Determination of PI3Kinase Kinase Enzyme Activity

Phosphoinositide 3 kinases (PI3K) belong to a class of lipid kinasesthat play a critical role in the regulation of several key cellularprocesses. The PI3K are capable of phosphorylating the 3-hydroxyposition of phosphoinositols thereby generating second messengersinvolved in downstream signalling events. The homogenous time resolvedfluorescence (HTRF) assay allows detection of 3,4,5-triphosphate (PIP3)formed as a result of phosphorylation of phosphotidylinositol4,5-biphosphate (PIP2) by PI3K isoforms such as α, β, γ or δ. PI3Kisoform activity for α, β, γ or δ was determined using a PI3K humanHTRF™ Assay Kit (Millipore, Billerica, Mass.) with modifications. Allincubations were carried out at room temperature. Briefly, 0.5 μl of 40×inhibitor (in 100% DMSO) or 100% DMSO were added to each well of a384-well black plate (Greiner Bio-One, Monroe, N.C.) containing 14.5 μl1× reaction buffer/PIP2 (10 mM MgCl₂, 5 mM DTT, 1.38 μM PIP2) mix withor without enzyme and incubated for 10 min. After the initialincubation, 5 μl/well of 400 μM ATP was added and incubated for anadditional 30 minutes. Reaction was terminated by adding 5 μl/well stopsolution (Millipore, Billerica, Mass.). Five microliters of detectionmix (Millipore, Billerica, Mass.) were then added to each well and wasincubated for 6-18 h in the dark. HRTF ratio was measured on amicroplate reader (BMG Labtech., Germany) at an excitation wavelength of337 nm and emission wavelengths of 665 and 620 nm with an integrationtime of 400 psec.

TABLE 2 % inhibition % inhibition % inhibition % inhibition (PI3kα)(PI3kβ) (PI3kγ) (PI3kδ) 1 IC50 1 IC50 300 IC50 300 IC50 Example uM (nM)uM (nM) nM (nM) nM (nM)  1. C — C − − − B −  2. D — D − − − B −  3. C —D − B +++ B ++++  4. — — — − − − — −  5. C >10000 D ++ − − B −  6.D >10000 C − A ++++ A +++++  7. C — B − − +++++ — +++++  8. D — B ++ −+++++ — +++++  9. C — C − A ++++ A +++++  9a. D — C − − +++++ — +++++ 9b. D — C − − ++ — ++ 10. C — D − A +++ C − 11. B — B − C − B − 12. D —C − A +++ C − 13. D — D − B − A +++++ 14. C — D − A ++++ A ++++ 15. — —— − D − D − 16. C — D − D − A ++++ 17. D — C − C − A − 18. D — D − B − A++++ 19. C — C − A − B − 20. D — C − D − A ++++ 21. — — — − D − C − 22.C — D − C − A − 23. D — C − A +++++ A ++++ 24. D — B − C − — − 25. D — C− A +++++ — − 26. D — C − A ++++ — − 27. D — C − B C − 28. D — C − B B −29. D — C − B C − 30. C — D − D C − 31. C — C − B B − 32. D — B − B D −33. D — C − B B − 34. D — C − B B − 35. — — — − C D 36. D — B − A C −37. D — C − B D − 38. C — C − D B − 39. C — B − D C −− 40. C — B − D B −41. C — C − B B 42. — — — − − − 43. — — — − − −− 44. D — D − C C −−− 45.— — — − C B 46. D — B − B C − 47. — — — − D D − 48. — — C − A +++++ B −49. B — B − B B −− 50. D — C − B A 51. — — — − B − C − 52. C — B − B − B− 53. — — — − B − D 54. C — C − B − B − 55. — — — − B − C 56. D — B − B− D − 57. — — — − B − D − 58. D — B − C − B − 59. — >10000 C + − +++++ —+++ % inhibition % inhibition % inhibition % inhibition (PI3kα) (PI3kβ)(PI3kγ) (PI3kδ) 1 IC50 1 IC50 100 IC50 100 IC50 Example uM (nM) uM (nM)nM (nM) nM (nM) 60. D — C − C − C − 61. C — C B − C − 62. D — B − C − B− 63. C — D − C − C − 64. — — C C − B − 65. C — C − B − D − 66. C — C −C − C − 67. — — — − − — − 68. C — B − B − C − 69. — — C − A − B − 70. D— C − C − C − 71. — — — − C − D 72. — — — −− C − D −− 73. — — — − C − C− 74. D C C B 75. D C 76. D C C C 77. C B C B ++++ 78. D C − B ++++ 79.C C C D 80. B C C B 81. C C C B 82. C C C C 83. A +++++ A +++++ 84. C +B +++++ 85. D C C C 86. D — C + B 87. C B D B +++ 88. 89. 90. 91. C C92. D D 93. D C 94. C C C C 95. D C 96. D D 97. C C C C 98. 99. C C 100.B B B ++++ C +++ 101. B C B +++ D 102. C B C D 103. C D 104. C D 105. CD 106. C D 107. D C C D 108. C D C C 109. D C 110. D C B ++++ A +++++111. — D C C 112. B D B B 113. C D B ++++ B +++++ 114. D — B B 115. C DC C 116. D D 117. B — C C 118. C D C C 119. C D 120. D D 121. C C B D122. D C 123. D C D B 124. C D D C 125. D — − C 126. D C D B 127. D B DB 128. C B C ++++ B ++++ 129. D C C D 130. C C C 131. C D C C 132. C B133. B B C 134. D C 135. C C 136. C C 137. D B D C

Data were analyzed using Graphpad Prism (Graphpad software; San DiegoCalif.) for IC₅₀ determination. Examples 1-59 were tested at 1 uM forPi3kα & Pi3kβ and at 0.3 uM for γ and δ. Examples 60-137 were tested at1 uM for Pi3kα & Pi3kβ and at 0.1 uM for γ and δ. Percent inhibition wascalculated based on the values for the blank and enzyme controls. Theresults are as provided in Table 2 (wherein D=0 to 25%; C=>25 to 50%;B=>50 to 75%; A=>75 to 100%; +++++=<50 nM; ++++=>50 to <100 nM; +++=>100to <300 nM; ++=>300 to <500 nM; +=>500 nM)

Assay 2: In Vitro Cell Proliferation Assay in Leukemic Cell Lines

Growth inhibition assays were carried out using 10% FBS supplementedmedia. Cells were seeded at a concentration of 5000-20,000 cells/well ina 96-well plate. Test compound at a concentration range from 0.01 to10000 nM were added after 24 h. Growth was assessed using the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dyereduction test at 0 h (prior to the addition of the test compound) and48 h after the addition of test compound. Absorbance was read on aFluostar Optima (BMG Labtech, Germany) at a wave length of 450 nm. Datawere analysed using GraphPad Prism and % inhibition due to the testcompound compared to the control was calculated accordingly. Exemplarycompounds of the present invention when tested @ 1 uM in THP-1; DLBCL;HL-60; MOLT-4, RPMI8226 and TOLEDO cell lines showed a 20 to 80%inhibition.

Assay 3: Inhibition of AKT Phosphorylation in Leukemic Cell Lines:

Inhibition of AKT phosphorylation in leukemic cell lines: THP-1, HL-60,MOLT-4, RPMI-8226, or DLBCL cells were incubated with desiredconcentrations of compound for 48 h. Cells were lysed and pAKT wasdetermined by Western Blotting. Bands were quantified using ImageJ andnormalized to actin. Exemplary compounds of the present invention whentested @ 1 uM in showed a 50 to 90% inhibition.

Assay 4: Inhibition of PI3Kδ Signalling in Basophils from Human WholeBlood

PI3Kδ signalling in basophils manifested by an alteration of anti-FcER1induced CD63 expression is a useful pharmacodynamic marker determinedusing the Flow2CAST® kit (Buhlmann Laboratories, Switzerland). Briefly,it involves the following steps:

-   -   Mix the anti-coagulated blood sample by inverting the        venipuncture tube several times    -   Prepare fresh and pyrogen-free 3.5 ml polypropylene or        polystyrene tubes suitable for Flow Cytometry measurements    -   Add 49 μl of patient's whole blood to each tube.    -   Add 1 μl of 10% DMSO (background) or compound (10% DMSO) to the        assigned tubes and mix gently. Incubate at room temperature for        15 min    -   Pipet 50 μl of the Stimulation buffer (background) or anti-FcεRI        Ab to each tube    -   Add 100 μl of Stimulation Buffer to each tube    -   Mix gently. Add 20 μl Staining Reagent (1:1 mix of FITC-CD63 and        PE-CCR3) to each tube    -   Mix gently, cover the tubes and incubate for 15 minutes at        37° C. in a water bath. (using an incubator will take about 10        minutes longer incubation time due to less efficient heat        transfer)    -   Add 2 ml pre-warmed (18-28° C.) Lysing Reagent to each tube, mix        gently    -   Incubate for 5-10 minutes at 18-28° C.    -   Centrifuge the tubes for 5 minutes at 500×g    -   Decant the supernatant by using blotting paper    -   Resuspend the cell pellet with 300-800 μl of Wash Buffer    -   Vortex gently and acquire the data on the flow cytometer within        the same day.    -   Percent CD63 positive cells within the gated basophil population        are to be determined in different treatment groups and        normalized to vehicle control.

Assay 5: Inhibition of Apoptosis in Leukemic Cell Lines Apoptosis inLeukemic Cells was Determined Using an In-Situ Caspase 3 Kit (Millipore,US) as Outlined Below:

-   -   Seed leukemic cells—at a density of 1×10⁶ cells/well in a 6 well        plate    -   Add test compound/DMSO at desired concentrations    -   Incubate the plate for 24 hrs at 37° C. in 5% CO₂ incubator    -   Collect cells in a 2 ml centrifuge tube    -   Add 1.6 μL of freshly prepared 5×FLICA reagent and mix cells by        slightly flicking the tubes    -   Incubate tubes for 1 hour at 37° C. under 5% CO₂    -   Add 2 ml of 1× wash buffer to each tube and mix    -   Centrifuge cells at <400×g for 5 minutes at room temperature.    -   Carefully remove and discard supernatant, and gently vortex cell        pellet to disrupt any cell-to-cell clumping.    -   Resuspend cell pellet in 300 ul of 1× wash buffer    -   Place 100 μL of each cell suspension into each of two wells of a        black microtiter plate. Avoid creation of bubbles.    -   Read absorbance of each microwell using an excitation wavelength        of 490 nm and an emission wavelength of 520 nm    -   Percent increase in caspase-3 activity manifested by an increase        in fluorescence compared to the control blank is to be        calculated.

Assay 6: Lipopolysaccharide Induced Pulmonary Neutrophilia in MaleSprague-Dawley Rat Model:

An exaggerated recruitment and subsequent activation of neutrophil islikely to be important for the development and course of severalinflammatory diseases in the airways and lungs, such as severe asthma,chronic obstructive pulmonary disease, cystic fibrosis, and acuterespiratory distress syndrome. The mechanisms by which neutrophilcontribute to these diseases may involve the release of proteolyticenzymes, such as neutrophil elastase, and free oxygen radicals. Whenreleased, these compounds can cause bronchoconstriction, bronchialhyperreactivity, hyper-secretion, epithelial damage, and tissueremodelling in the airways. After the quarantine period, fasted animalsare to be randomized and divided into various groups depending on theirbody weights. Test compound is to be prepared as a suspension in avehicle consisting of 0.5% methylcellulose in which Tween 80 as asuspending agent. The compound or vehicle is to be administered by oralgavage in a volume of 10 mL/kg. Animals are to be anaesthetized withketamine and LPS solution was administered intratracheally one hourafter compound administration at a dose of 1 mg/kg. 6 h after LPSinstillation, animals are to be exsanguinated under anaesthesia, andthen trachea is to be cannulated and the lungs are to be lavaged with5-ml aliquots of heparinised PBS (1 unit/ml) four times through trachealcannula (total volume 20 ml). BAL fluid has to be stored at 2-8° C.until assayed for total cell and differential leukocyte count.Bronchioalveolar fluid is to be centrifuged (500×g for 10 min) and theresulting cell pellet is to be resuspended in 0.5 ml of heparinisedsaline. The total numbers of white blood cells are to be determined inBAL fluid or blood by using a blood cell counter and has to be adjustedto 1×10⁶ cell/ml. Differential cell count has to be calculated manually.One hundred microliters of the cell suspension is to be centrifugedusing cytospin 3 to prepare a cell smear. The cell smear has to bestained with a blood staining solution for differentiation and slideshave to be microscopically observed to identify eosinophil according totheir morphological characteristics. The number of each cell type among300 white blood cells in the cell smear is to be determined andexpressed as a percentage. The number of eosinophil in each BALf orblood is to be calculated.

Assay 7: Lipopolysaccharide-Mediated Rat Air Pouch Model ofInflammation:

Leukocyte recruitment and the formation of pro-inflammatory mediators,including different cytokines, are the hallmark of an inflammatoryresponse. The air-pouch model was originally developed as a facsimilesynovium for the study of inflammatory processes that occur in RA. Themodel allows the differential quantification of leukocyte species thataccumulate in the air-pouch wall (tissue) as well as those thattransmigrate into the air-pouch cavity (lavage), and it allows thecharacterization of the chemokines and adhesion molecules responsiblefor diapedesis induced by a variety of inflammatory stimuli.

Male Wistar rats (175-200 g) are to be acclimatized for seven days priorto the start of the experiment. Animals are then to be randomlydistributed to various groups based on their body weights. Animals areto be anaesthetised with ether and subcutaneous air pouches are to beformed by injecting 20 ml of sterile air under the skin in theintra-scapular area (day 0) and maintained with a second 10-ml injectionof sterile-filtered air on day 4. On day 6, oral treatment is to becommenced 1 h prior to induction of inflammation by s.c. injection ofLPS solution on day 6. A volume of 5-ml of LPS solution dissolved insterile saline (10 μg/kg) is to be injected into each pouch. Samples ofpouch fluid are to be taken at 6 h after administration of LPS byflushing the pouch with 5 ml of sterile saline and withdrawing 4 ml offluid. The numbers of leukocytes present in pouch fluid has to bedetermined microscopically using a haemocytometer. Differential cellcontent has to be determined by microscopic examination of fluid smearsstained with Diff-Quik.

Assay 8: Lipopolysaccharide Induced TNF-α Production:

Fasted female wistar rats are to be randomized in to different groupsdepending on their body weights. Test compound has to be prepared as asuspension in a vehicle consisting of 0.5% methylcellulose. The compoundor vehicle is to be administered by oral gavage in a volume of 10 mL/kg.LPS solution is to be administered intraperitoneally one hour aftercompound administration at a dose of 0.3 mg/kg. Blood has to becollected in serum separator tubes via cardiac puncture ninety minutesafter LPS injection. Serum has to be separated and stored at −20° C. andwill be analysed for TNFα by ELISA.

Assay 9: Ovalbumin Induced Pulmonary Eosinophilia in Male Guinea Pigs:

Airway inflammation and hyper-responsiveness (AHR) are hallmarks anddistinguishing features of bronchial asthma. Provocation ofpre-sensitized mice with the same allergen induces airway inflammationwith preferential eosinophilic infiltration and, as a consequence, AHR.Pulmonary eosinophilia and airway remodelling in conjunction withaltered neural control of airway tone and airway epithelial desquamationmay contribute to AHR in asthma. After the quarantine period, 0.3 mL ofblood samples is to be collected from orbital vein by retro-orbitalplexus method from each individual animal and analysed on a cellanalyser (ADVIA 2120, Siemens). Based on their total cell count, guineapigs are to be randomized and divided into various groups. Ear pinna isto be marked with an indelible marking pen for identification. On day 0,weights are to be recorded and animals are then to be sensitized with 50μg of Ovalbumin and 10 mg of alum solution (1 mL) intraperitoneally. Onday 7 and day 14, the above sensitization protocol has to be repeated.On day 18, animals are to be treated with test compound byoral/intranasal route. On day 19, & 20, animals are to be treated withtest compound by oral/intranasal administration and exposed to 0.5% w/vOvalbumin for 10 min using ultrasonic nebulizer with flow rate of 0.2 mlper min. On day 21, fasted animals are to be treated with test compoundby oral/intranasal administration and 15 min after dosing, animals areto be nebulized with 1% w/v Ovalbumin solution for 10 min. Control groupanimals are to be treated with 0.5% w/v methyl cellulose (vehicle). Shamcontrol groups are to be sensitized with 10 mg of alum on day 0, 7 & 14and exposed to saline solution with the same nebulization rate on d19,d20 & d21. Twenty four hours after OVA challenge, blood samples and BALfluid has to be collected. Samples are to be analysed for total cellcount by using blood analyser (ADVIA 2120, Siemens) and differentialleukocyte count is to be done manually.

Assay 10: Collagen Induced Arthritis in Wistar Rats:

Female wistar rats are to be acclimatized for seven days prior to thestart of the experiment and are randomly distributed to various groupsbased on their body weights. On day 0, animals are to be treated byintradermal injection of 500 μg of bovine collagen type II emulsifiedwith complete Freund's adjuvant (IFA) containing MTB (4 mg/mL) deliveredat the base of the tail. On day 7 after primary immunization, animalsare to be treated by booster injection of 300 μg CII in incompleteFreund's adjuvant by intradermal injection at the base of the tail.Onset of arthritis in ankle joints usually became visually apparentbetween days 12 and 14. Animals are to be treated with test compound orvehicle (orally administered) from the day after onset of arthritisuntil end of the experiment (day 28) as a therapeutic group. ArthritisScores have to be taken by visually examination for signs of jointinflammation regularly throughout the study period. Body weights and pawvolumes, paw thickness have to be taken on day 0, 3, 7, 10, 12, 14, 1721, 24 and 28. On d28, at the end of the study, blood has to bewithdrawn at necropsy and processed to serum or plasma and all jointsare to be taken and both fore paw and hind paws are to be fixed in 10%formalin for histopathology analysis after taking the small piece oftissue from each joint and stored at −80° C. for cytokine analysis intissue homogenate. Clinical Scoring Criteria for Fore and Hind Paws:0=normal;

1=1 hind or fore paw joint affected or minimal diffuse erythema andswelling; 2=2 hind or fore paw joints affected or mild diffuse erythemaand swelling; 3=3 hind or fore paw joints affected or moderate diffuseerythema and swelling; 4=Marked diffuse erythema and swelling, or =4digit joints affected); 5=Severe diffuse erythema and severe swellingentire paw, unable to flex digits)

Assay 11: Acute CSE Induced Cell Infiltration in Male Balb/c Mice:

Animals are to be acclimatized for seven days prior to the start of theexperiment. Animals are to be randomly distributed to various groupsbased on their body weights. On day 1, mice are to be administered bytest compound or vehicle by oral/intranasal route and after 1 hr testcompound administration animals are to be anaesthetised with ether andcigarette smoke extract is to be administered by intranasal route involume of 50 μl/mouse and repeated the CSE exposure to animals dailyafter the test compound administration for four days (d1 to d4). On day5, 24 hours after last CSE exposure animals are to be exsanguinatedunder anesthesia, and the trachea is to be cannulated and the lungs arelavaged with 0.5-ml aliquots of heparinised PBS (1 unit/ml) four timesthrough tracheal cannula (total volume 2 ml). BAL stored at 2-8° C.until assayed for total cell and differential leukocyte count.Bronchioalveolar fluid is to be centrifuged (500×g for 10 min) and theresulting cell pellet has to be resuspended in 0.5 ml of heparinisedsaline. The total number of white blood cells is to be determined in BALfluid and blood using a blood cell counter and adjusted to 1×10⁶cell/ml. Differential cell count is to be calculated manually. Fortymicroliters of the cell suspension is to be centrifuged using cytospin 3to prepare a cell smear. The cell smear is to be stained with a bloodstaining solution for differentiation and microscopically has to beobserved to identify eosinophil according to their morphologicalcharacteristics. The number of each cell type among 300 white bloodcells in the cell smear are to be determined and has to be expressed asa percentage, and the number of neutrophils & macrophages in each BALfare to be calculated.

Assay 12: Sub-Chronic CSE Induced Cell Infiltration in Male Balb/c Mice:

Animals are to be acclimatized for seven days prior to the start of theexperiment. Animals are to be randomly distributed to various groupsbased on their body weights. On day 1, animals are to be anaesthetisedwith ether and cigarette smoke extract is to be administered byintranasal route in volume of 50 μl/mouse and repeated the CSE exposureto animals daily for eight days (di to d8). On day 9, mice are to beadministered by test compound or vehicle by oral/intranasal route andafter 1 hr test compound administration animals are to be anaesthetisedwith ether and cigarette smoke extract is to be administered byintranasal route in volume of 50 μl/mouse and animals are to be exposedto CSE daily after the test compound administration for next three days(d9 to d11), on day 12, twenty four hours after last CSE exposureanimals are to be exsanguinated under anesthesia, and the trachea is tobe cannulated and the lungs are to be lavaged with 0.5-ml aliquots ofheparinised PBS (1 unit/ml) four times through tracheal cannula (totalvolume 2 ml). BAL stored at 2-8° C. until assayed for total cell anddifferential leukocyte count. Bronchioalveolar fluid was centrifuged(500×g for 10 min) and the resulting cell pellet is to be resuspended in0.5 ml of heparinised saline. The total numbers of white blood cells areto be determined in BAL fluid and blood using a blood cell counter andadjusted to 1×10⁶ cell/ml. Differential cell count was calculatedmanually. Forty microliters of the cell suspension is to be centrifugedusing cytospin 3 to prepare a cell smear. The cell smear is to bestained with a blood staining solution for differentiation andmicroscopically observed to identify eosinophil according to theirmorphological characteristics. The number of each cell type among 300white blood cells in the cell smear has to be determined and expressedas a percentage, and the number of neutrophils & macrophages in eachBALf are to be calculated.

Assay 13: Reversal of Corticosteroid Insensitivity in Cigarette SmokeExtract Induced Pulmonary Inflammation (COPD) Model:

Female Balb/c mice are to be acclimatized for seven days prior to thestart of the experiment. Animals are then to be randomly distributed tovarious groups based on their body weights. On day 1, animals are to beanaesthetised with ether and cigarette smoke extract is to beadministered by intranasal route in volume of 50 μl/mouse and animalsare to be exposed to CSE daily for next five days (d1 to d6). On day 7,mice are to be administered by dexamethasone at 10 mg/kg by oral gavageand 60 mins later, mice are to be administered with CSE by intranasalroute and it has to be repeated for next four days (d7 to d11). From day9 to day 11, animals are to be administered by test compound or vehicleby oral/intranasal route and 30 mins after dexamethasone administrationand 30 mins later animals are to be anaesthetised with ether andcigarette smoke extract is to be administered by intranasal route involume of 50 μl/mouse and animals are to be exposed to CSE daily afterthe test compound administration for next two days (i.e. d9 to d11), ond12, twenty four hours after last CSE exposure animals are to beexsanguinated under anesthesia, and the trachea is to be cannulated andthe lungs are to be lavaged with 0.5-ml aliquots of heparinised PBS (1unit/ml) four times through tracheal cannula (total volume 2 ml). BALhas to be stored at 2-8° C. until assayed for total cell anddifferential leukocyte count. Bronchioalveolar fluid is to becentrifuged (500×g for 10 min) and the resulting cell pellet has to beresuspended in 0.5 ml of heparinised saline. The total number of whiteblood cells is to be determined in BAL fluid and blood using a bloodcell counter and adjusted to 1×10⁶ cell/ml. Differential cell count isto be calculated manually. Forty microliters of the cell suspension isto be centrifuged using cytospin 3 to prepare a cell smear. The cellsmear is to be stained with a blood staining solution fordifferentiation and microscopically has to be observed to identifyeosinophil according to their morphological characteristics. The numberof each cell type among 300 white blood cells in the cell smear are tobe determined and will be expressed as a percentage, and the number ofneutrophils and macrophages in each BAL fluid are to be calculated.

Assay 14: Acute Cigarette Smoke Induced Cell Infiltration in Male Balb/cMice:

Animals are to be acclimatized for seven days prior to the start of theexperiment. Animals are then to be randomly distributed to variousgroups based on their body weights. On day 1, mice is to be administeredtest compound or vehicle by oral/intranasal route and after 1 hr testcompound administration animals are to be placed in whole body exposurebox. On day 1 and d2 mice are exposed to the mainstream smoke of 6cigarettes and of 8 cigarettes on day 3, and of 10 cigarettes on day 4.Exposure to the smoke of each cigarette lasts for 10 min (cigarette areto be completely burned in the first two minutes and followed by an airflow with animal ventilator and next 20 min exposure with fresh roomair. After every second cigarette an additional break of 20 min withexposure to fresh room air is to be conducted. Control animals are to beexposed to room air chamber. From day 1 to d4 animals are administeredby test compound either oral or intranasal route. On day 5, 24 hoursafter last cigarette smoke (CS) exposure animals are exsanguinated underanesthesia, and the trachea is to be cannulated and the lungs arelavaged with 0.5-ml aliquots of heparinised PBS (1 unit/ml) four timesthrough tracheal cannula (total volume 2 ml). Bronchioalveolar (BAL)collected is to be stored at 2-8° C. until assayed for total cell anddifferential leukocyte count. BAL fluid is to be centrifuged (500×g for10 min) and the resulting cell pellet is resuspended in 0.5 ml ofheparinised saline. The total number of white blood cells is to bedetermined in BAL fluid and blood using a blood cell counter andadjusted to 1×10⁶ cell/ml. Differential cell count is calculatedmanually. Forty microliters of the cell suspension is centrifuged usingcytospin 3 to prepare a cell smear. The cell smear is stained with ablood staining solution for differentiation and microscopically observedto identify eosinophil according to their morphological characteristics.The number of each cell type among 300 white blood cells in the cellsmear are to be determined and expressed as a percentage, and the numberof neutrophils & macrophages in each BAL fluid are to be calculated.

Assay 15: Ovalbumin-Induced Nasal Eosinophil and Neutrophil Accumulationin Mice:

Animals are to be acclimatized for seven days prior to the start of theexperiment. Animals are then to be randomly distributed to variousgroups based on their body weights. Animals are to be immunized with OVA(40 μg/kg i.p.) on day 1 and 5. In order to elicit local inflammatoryresponses in the nose, mice are to be repeatedly challengedintra-nasally (10 μL/per nostril) on days 12-19 with OVA (3% OVA insaline). On day 19 non-fasted mice are to be dosed intra-nasally (10μL/nostril) with either vehicle or test compound 2 hours before to thestart of the final OVA challenge. Two hrs later, each animal is to bereceived a final intranasal OVA (3%) challenge). After a further 8 hr,each animal is to be anaesthetized and nasal lavage is to be carried outby instilling 1 ml of PBS into the posterior nares via a rostrallyimplanted tracheal cannula extending to a position that is approximately1 mm before the posterior nares. This procedure has to be repeated togive a yield of approximately 2 ml of lavage fluid. Total cell numbersin the nasal lavage fluid samples are to be measured using ahaemocytometer. Cytospin smears of the nasal lavage fluid samples are tobe prepared by centrifugation at 1200 rpm for 2 min at RT and stainedusing a Diff-Quik stain system (Dade Behring) for differential cellcounts. Cells are to be counted using oil immersion microscopy.

Assay 16: Poly-I:C-Induced Cell Accumulation in Mice:

Specific pathogen-free A/J mice (males, 5 weeks old) are to beacclimatized for seven days prior to the start of the experiment.Animals are then to be randomly distributed to various groups based ontheir body weights. Animals are to be administered with poly (I:C)-LMW(poly-IC; 1 mg/mL, 40 μL) intranasally twice daily for 3 days underanaesthesia with 3% isoflurane. Animals are to be treated with testcompound by intra-nasally (35 μL of solution in 50% DMSO/PBS) 2 hrbefore each poly-I:C treatment. Twenty four hr after the last poly-I:Cchallenge, animals are to be anesthetized, the trachea has to becannulated and BALF is to be collected. The concentrations of alveolarmacrophages and neutrophils in BALF are to be determined by using ablood cell counter and adjusted to 1×10⁶ cell/ml. Differential cellcount is calculated manually. Forty microliters of the cell suspensionis centrifuged using cytospin 3 to prepare a cell smear. The cell smearis stained with a blood staining solution for differentiation andmicroscopically observed to identify eosinophil according to theirmorphological characteristics. The number of each cell type among 300white blood cells in the cell smear are to be determined and expressedas a percentage, and the number of neutrophils & macrophages in each BALfluid are to be calculated.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above. It is intended that theappended claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

All publications and patent and/or patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated herein by reference.

1-37. (canceled)
 38. A method for the treatment of a PI3K associateddisease or disorder, comprising the step of administering to a subjectin need thereof an effective amount of the compound of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein each occurrence of R is independently selected fromhydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)R^(y), —NR^(x)CONR^(x)R^(y),—N(R^(x))SOR^(x), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(x)R^(y), —OR^(x)C(O)OR^(x)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R′, —ONO₂, wherein R^(x), R^(y)and R^(z) in each of the above groups can be hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted heterocyclylalkyl ring, or substituted or unsubstitutedamino, or (i) any two of R^(x) and R^(y) may be joined to form asubstituted or unsubstituted, saturated or unsaturated 3-14 memberedring, which may optionally include heteroatoms which may be the same ordifferent and are selected from O, NR^(z) or S, or (ii) any two of R^(x)and R join to form a oxo (═O), thio (═S) or imino (═NR^(f)) (whereinR^(f) is hydrogen or substituted or unsubstituted alkyl); R¹ and R² maybe the same or different and are independently selected from hydrogen,halogen, and substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, and substituted orunsubstituted heterocyclyl, or both R¹ and R² directly bound to a commonatom, may be joined to form an oxo group (═O) or a substituted orunsubstituted, saturated or unsaturated 3-10 member ring (including thecarbon atom to which R¹ and R² are bound), which may optionally includeone or more heteroatoms which may be the same or different and areselected from O, NR^(a) and S; Cy¹ is selected from substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; Cy² is selected from a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R′ andR^(d) are independently hydrogen, halogen, hydroxy, cyano, substitutedor unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR′ (wherein R^(c)is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a) and R^(b) aredirectly bound to a common atom, they may be joined to form an oxo group(═O) or form a substituted or unsubstituted, saturated or unsaturated3-10 member ring (including the common atom to which R^(a) and R^(b) aredirectly bound), which may optionally include one or more heteroatomswhich may be the same or different and are selected from O, NR^(d)(wherein R^(d) is hydrogen or substituted or unsubstituted (C₁₋₆)alkyl)or S; Y is selected from O, S, and NR^(a); and q is 0, 1 or
 2. 39. Amethod of claim 38, wherein the compound selected from:2-(6-Amino-9H-purin-9-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one;2-((4-Amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one;2-((4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;2-(1-(4-amino-3-(benzofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(+)-2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-isopropyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(piperidin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(2-hydroxyethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(isopropylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(dimethylamino)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;2-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(dimethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(6-isopropoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate;2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate;2-(1-(4-amino-3-(4-(1-benzhydrylazetidin-3-yloxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;2-(1-(4-amino-3-(4-isobutylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzenesulfonamide;4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-N-isopropylbenzamide;2-(1-(4-amino-3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methanesulfonamide;4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzenesulfonamide;4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzenesulfonamide;2-(1-(4-amino-3-(2-isopropoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzenesulfonamide;methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carboxylate;2-(1-(4-amino-3-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;methyl4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorobenzoate;2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyl-4H-chromen-4-one;2-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one4-methylbenzenesulfonate;(+)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(R)/(S)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;tert-butyl(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamate;2-(1-(4-amino-3-(2,4-dimethylthiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)isobutyramide;N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamide;2-(1-(4-(dimethylamino)-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;N-(2-fluoro-4-(1-(1-(5-fluoro-3-(4-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;N-(2-fluoro-4-(1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onesulphate;(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-onecamphorsulphonate;2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;2-(1-(4-(dimethylamino)-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-2-(1-(3-(3-fluoro-4-morpholinophenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;(S)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;(R)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;(+)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;5-fluoro-3-(4-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one;5-fluoro-3-(4-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one;2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-3-(3-fluorophenyl)-2-(1-(3-(3-methyl-1H-indazol-6-yl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(+)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(−)-2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(S)/(R)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-3-(3-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-5-morpholino-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-morpholino-3-phenyl-4H-chromen-4-one;6-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one;5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one;2-(1-(3-(4-acetyl-3-fluorophenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;5-fluoro-3-(3-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one;(S)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(4-amino-3-(3-chloro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;N-(3-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide;(S)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(4-ethoxy-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one;(R)-5-fluoro-3-(3-fluorophenyl)-2-(1-(2-methoxy-9H-purin-6-ylamino)ethyl)-4H-chromen-4-one;(S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one;2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-o-tolyl-4H-chromen-4-one; andpharmaceutically acceptable salts thereof.
 40. A method of claim 38,further comprising the step of administering simultaneously orsequentially to a subject in need thereof at least one other anti-canceragent, anti-inflammatory agent, immunosuppressive agent, steroid,non-steroidal anti-inflammatory agent, antihistamine, analgesic, or amixture thereof.
 41. A method of claim 38, wherein the PI3K associateddisease, disorder or condition is an immune system-related disease, adisease or disorder involving inflammation, cancer or otherproliferative disease, a hepatic disease or disorder, or a renal diseaseor disorder.
 42. A method of claim 38, wherein the PI3K associateddisease, disorder or condition is selected from inflammation,glomerulonephritis, uveitis, hepatic diseases or disorders, renaldiseases or disorders, chronic obstructive pulmonary disease, rheumatoidarthritis, inflammatory bowel disease, vasculitis, dermatitis,osteoarthritis, inflammatory muscle disease, allergic rhinitis,vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema,allogeneic or xenogeneic transplantation, graft rejection,graft-versus-host disease, lupus erythematosus, pulmonary fibrosis,dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolyticanemia, cystic fibrosis, chronic relapsing hepatitis, primary biliarycirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis,asthma, Sjogren's syndrome, organ transplant rejection, multiplesclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolyticanemia, pernicious anemia, autoimmune thrombocytopenia, temporalarteritis, anti-phospholipid syndrome, vasculitides such as Wegener'sgranulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis,pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerativecolitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 orimmune-mediated diabetes mellitus, Grave's disease, Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder ofthe adrenal gland, systemic lupus erythematosus, polymyositis,dermatomyositis, ankylosing spondylitis, transplant rejection, skingraft rejection, arthritis, bone diseases associated with increased boneresorption, ileitis, Barrett's syndrome, adult respiratory distresssyndrome, chronic obstructive airway disease, corneal dystrophy,trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis,gingivitis, periodontitis, tuberculosis, leprosy, uremic complications,nephrosis, sclerodermatitis, psoriasis, chronic demyelinating diseasesof the nervous system, AIDS-related neurodegeneration, Alzheimer'sdisease, infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis viral or autoimmuneencephalitis, autoimmune disorders, immune-complex vasculitis, systemiclupus and erythematodes, systemic lupus erythematosus (SLE),cardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis, preeclampsia, chronic liver failure, brain and spinalcord trauma, and cancer.
 43. A method of claim 38, wherein the PI3Kassociated disease, disorder or condition is selected from hematopoietictumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin'slymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett'slymphoma; hematopoietic tumors of myeloid lineage, acute myelogenousleukemias, chronic myelogenous leukemias, myelodysplastic syndrome,promyelocytic leukemia; carcinoma of the bladder, carcinoma of thebreast, carcinoma of the colon, carcinoma of the kidney, carcinoma ofthe liver, carcinoma of the lung, small cell lung cancer, esophagealcancer, gall bladdercancer, ovarian cancer, pancreatic cancer,stomachcancer, cervical cancer, thyroidcancer, prostatecancer,skincancer, squamous cell carcinoma; tumors of mesenchymal origin,fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheralnervous system, astrocytoma, neuroblastoma, glioma, schwannoma;melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer, and Kaposi'ssarcoma.
 44. A method of claim 38, wherein the PI3K associated disease,disorder or condition is selected from chronic obstructive pulmonarydisease, asthma, rheumatoid arthritis, chronic bronchitis, inflammatorybowel disease, allergic rhinitis, lupus erythematosus and ulcerativecolitis.
 45. A method of claim 38, wherein the PI3K associated disease,disorder or condition is selected from hematopoietic tumors of lymphoidlineage, leukemia, acute lymphocytic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma,non-Hodgkins lymphoma, chronic lymphocytic leukemia, hairy cell lymphomaand Burkett's lymphoma, hematopoietic tumors of myeloid lineage, acutemyelogenous leukemias, chronic myelogenous leukemias, myelodysplasticsyndrome, promyelocytic leukemia or multiple myelomas which includessmoldering multiple myeloma, nonsecretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma.
 46. A method of claim 38, wherein the PI3K associateddisease, disorder or condition is selected from Chronic LymphocyticLeukemia (CLL), Lymphoma Non-Hodgkin (NHL), Acute Myeloid Leukemia(AML), Multiple Myeloma (MM), Small Lymphocytic Lymphoma (SLL), andIndolent Non-Hodgkin's Lymphoma (I-NHL).
 47. A method of inhibiting acatalytic activity of a phosphoinositol 3-kinase present in a cell,comprising contacting the cell with an effective amount of a compoundselected from2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or apharmaceutically acceptable salt, N-oxide or tautomer thereof.
 48. Themethod of claim 47, wherein the inhibition takes place in a subjectsuffering from a disease or disorder selected from cancer, a bonedisorder, an inflammatory disease, an immune disease, a nervous systemdisease, a metabolic disease, a respiratory disease, thrombosis, and acardiac disease.
 49. A method of treating asthma in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of a compound selected from2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or apharmaceutically acceptable salt, N-oxide or tautomer thereof.
 50. Amethod of treating chronic obstructive pulmonary disease in a subject inneed thereof comprising administering to the subject a therapeuticallyeffective amount of a compound selected from2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,(−)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or apharmaceutically acceptable salt, N-oxide or tautomer thereof.
 51. Amethod of inhibiting a catalytic activity of a phosphoinositol 3-kinasepresent in a cell, comprising contacting the cell with an effectiveamount of a compound selected from(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or apharmaceutically acceptable salt, N-oxide or tautomer thereof.
 52. Themethod of claim 51, wherein the inhibition takes place in a subjectsuffering from a disease or disorder selected from cancer, a bonedisorder, an inflammatory disease, an immune disease, a nervous systemdisease, a metabolic disease, a respiratory disease, thrombosis, and acardiac disease.
 53. A method of treating asthma in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of a compound selected from(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or apharmaceutically acceptable salt, N-oxide or tautomer thereof.
 54. Amethod of treating chronic obstructive pulmonary disease in a subject inneed thereof comprising administering to the subject need thereof atherapeutically effective amount of a compound selected from(+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or apharmaceutically acceptable salt, N-oxide or tautomer thereof.